Endoscope system for fluorescent observation

ABSTRACT

An endoscope system is disclosed for detecting fluorescent light emitted in the near-infrared region by a plurality of fluorescent labeling materials introduced into a living tissue. An illumination system generates illumination light in the wavelength range 600 nm-2000 nm which serves as excitation light for the plurality of fluorescent labeling materials, and a detection system that can separately detect different ones of the plurality of fluorescent light emissions that are emitted at different wavelengths from among the plurality of fluorescent labeling materials is provided. The endoscope system may include a conventional-type endoscope having an insertion section, or a capsule endoscope that wirelessly transmits image data. By superimposing the image data obtained using reflected light in the visible region and fluorescent light emitted by the fluorescent labeling materials, improved diagnostic capabilities are provided.

This application claims the benefit of priority of JP 2003-172361, filedin Japan on Jun. 15, 2003, and of JP 2004-176198, filed in Japan on Jun.14, 2004, the subject matters of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Prior art endoscopes have conventionally been used in diagnosis andtreatment where a fluorescent substance having an affinity to a lesion,such as cancer, has been previously administered into a subject's bodyand excitation light that excites the fluorescent substance is thenirradiated onto tissue of the subject so that fluorescent emissions fromthe fluorescent substance that deposits at the lesion can be detected.

For example, Japanese Laid-Open Patent Application H10-201707 describesa prior art endoscope wherein indocyanine green derivative labeledantibodies have been previously introduced into the living tissue. Thelesions then emit fluorescent light when excited by infrared light, withthe infrared light being readily transmitted by living tissue withoutdamaging the living tissue. This enables the lesions to be observed bydetecting the fluorescent light emissions while the light caused byself-fluorescence (autofluorescence) of the living tissues is blocked inorder to aid in preventing lesions that are deep inside the livingtissue from being overlooked.

Indocyanine green derivative labeled antibodies attach to human IgG as afluorescent agent and are excited by excitation light having a peakwavelength of approximately 770 nm. Such labeled antibodies producefluorescence having a peak wavelength of approximately 810 nm. JapaneseLaid-Open Patent Application H10-201707 illuminates living tissue ofinterest that has previously been administered such a fluorescent agentwith light from a light source having wavelengths in the range ofapproximately 770-780 nm, and then detects light wavelengths that areemitted from the living tissue in the wavelength range of approximately810-820 nm so as to determine the presence of a lesion.

It is a well known fact that the earlier cancer is detected in a patientthe less invasive the treatment; moreover, the treatment is generallymore effective so as to provide improved survivability. Early detectionof cancer in patients is a goal embraced by workers in the lifescience/medical field as well as by the population as a whole. However,cancer cells in the earliest stage show only meager morphologic changesfrom normal cells, and thus, conventional techniques that focus primaryon morphologic changes in cells for determining the presence of cancerare not applicable for detecting cancer in the earliest stage.

Furthermore, cancer in the earliest stage typically develops severalmillimeters deep within the surface of living tissue. In addition,living tissue scatters light in a sufficiently intense manner that theliving tissue layer above the cancerous region blocks observation of thecancer. This becomes a remarkably adverse factor in solving the problemof detecting cancer in the earliest stage. Of course, the fact that thetissues to be observed are within a living body is also an adversefactor.

Attempts have been made to develop a technique that combines usinginfrared light, which can reach deep inside living tissue with theinfrared light being minimally scattered or absorbed, with a technologythat introduces a plurality of different fluorescent labels into aplurality of different specific proteins. The proteins appear as cancerdevelops within livihg cells, and such a technique would enable thedetection of cancer in its earliest stage and should enable a diagnosisto be made of whether the cancer has become malignant. In addition toendoscopes, diagnosis systems for cancer include CT, MRI, and PETscanning devices. Each of these devices uses a sensor that is externallyprovided in order to depict in three dimensions the interior regions ofa human body and each is a non-invasive organ examination tool. Suchdevices can detect cancer once the cancerous region has grown to a sizeof approximately 1 cm or larger. However, the resolution of thesedevices is not yet sufficient to enable cancer to be detected in itsearliest stage or to enable a diagnosis to be made of whether the cancerhas become malignant.

Research in life science such as genomics and proteomics has determinedthat cancer develops as a pre-cancerous lesion and the lesion graduallygrows and transforms into metastatic, infiltrative cancer cells. Canceris a genetic disease, and it is believed that a succession of geneticmutations causes the cells to become malignant. Gene defects aretriggered by the expression (i.e., the presence) of specific proteins inthe cell. A diagnosis of malignancy concerning a tumor or cancer can bemade only when specific proteins for plural types of cancers arepresent, or when genes that cause defects are detected.

According to recent reports, tumors can be diagnosed as being eitherbenign or malignant when several types of proteins that are specificallyexpressed in cancer cells are detected. The diagnosis of the malignancyof a tumor is assured with improved accuracy if various additional typesof proteins are detected. Theoretically, plural cancer-specific proteinsin a living body can be labeled with different fluorescent lightproducing substances. Then, the different fluorescent light producingsubstances can be detected so as to determine the presence ofcancer-specific proteins in order to verify a malignancy.

Living tissue scatters light in a sufficiently intense manner thatilluminated living tissue is difficult to see through. However, livingtissue rarely scatters or absorbs significant amounts of light in thenear-infrared to infrared range. For this reason, near-infrared andinfrared wavelengths of light are often used in lesion diagnosistechniques. Light of this wavelength range is used as the excitationlight for the fluorescent labels so that fluorescent labels that aredistributed deep inside a living tissue will emit fluorescence, therebyaiding in the detection of cancer at an early stage.

In the present invention, plural cancer-specific proteins are labeledwith different fluorescent light producing substances that fluoresce inthe near-infrared to infrared range, and these wavelengths are thendetected using an endoscope so as to reveal the presence ofcancer-specific proteins in cells that may be several millimeters deepwithin a living body. It is desirable that the respective fluorescentlabels have narrow fluorescent wavelength emissions so that pluralfluorescent labels can be introduced and detected, thus increasing thenumber of types of cancer-specific proteins that can be detected andthereby improving the accuracy of such an endoscopic diagnosis.

Fluorescent labels that bind to cancer-specific proteins are introducedinto living tissues, and plural fluorescent wavelengths are detected sothat cancer-specific proteins that correspond to the fluorescentwavelengths can be detected. Thus, plural fluorescent labels can be usedfor fluorescence detection so that cancer in a patient can be diagnosedas being either benign or malignant at an earlier stage.

In prior art endoscopes, the wavelength used can be varied only byvarying the wavelength of the light source, and thus a technique forseparating plural wavelengths in the near-infrared range is notavailable in the detection component. Therefore, in prior artendoscopes, plural fluorescent wavelengths that emit fluorescence in thenear-infrared range when excited by illumination cannot be detected evenwhen such labels have been previously introduced into living tissue thatis to be observed.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to an endoscope system for endoscopicdiagnosis of a subject who has been administered, for example, multiplefluorescent labels that emit fluorescence of the near-infraredwavelength range. More specifically, the present invention provides anendoscope system wherein plural fluorescent labels that have beenpreviously introduced into living tissue can be separately detectedusing wavelengths in the near-infrared range.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given below and the accompanying drawings, whichare given by way of illustration only and thus are not limitative of thepresent invention, wherein:

FIG. 1 shows the overall structure of an embodiment of an endoscopesystem according to the present invention, characterized by having thecomponents that separate and detect plural fluorescent wavelengthspositioned within the endoscope tip section of an endoscope that uses animage pickup device (such a combination is sometimes termed an‘electronic endoscope’ or a ‘video endoscope’);

FIG. 2 shows in greater detail the structure of the light source opticalsystem 2 shown in FIG. 1;

FIG. 3 is an end view of a turret 22 (also shown in FIG. 2) that isprovided with two different band pass filters;

FIG. 4 shows the spectral transmittance of the band pass filter 27 a ofFIG. 3 that transmits primarily visible light (solid line) and of theband pass filter 27 b of FIG. 3 that transmits primarily near-infraredlight (dot-dash line);

FIG. 5 shows a layout of windows that are provided on a rotational disk23 of FIG. 2;

FIG. 6 shows exemplary spectral transmittances of optical filters thatare attached to the inner windows of the rotational disk shown in FIG.5;

FIG. 7 is a schematic illustration that shows the illumination system;

FIGS. 8(a)-8(d) show exemplary spectral intensity profiles of light forsequentially illuminating the living tissue 4 (illustrated in FIG. 1);

FIG. 9 illustrates the spectral reflectance of normal living tissue;

FIG. 10 shows the spectral transmittance of the excitation cut-offfilter 34 (shown in FIG. 1);

FIGS. 11(a)-11(d) show the spectral intensities of light entering theobjective lens 33 (FIG. 1) from living tissue when illumination light asshown in FIGS. 8(a)-8(d) is irradiated onto the living tissue afterfluorescent labels have been introduced into the living tissue;

FIG. 12 shows the structure of a two-layer, tunable Fabry-Perot etalonfilter;

FIG. 13 shows the spectral transmittance of the tunable filter structureshown in FIG. 12;

FIG. 14 is a cross-sectional view of a three-layer, tunable Fabry-Perotetalon filter;

FIG. 15 is a cross-sectional view of another three-layer, tunableFabry-Perot etalon filter;

FIGS. 16(a)-16(c) show different spectral transmittances of a tunablefilter 35 (shown in FIG. 1) that may be used in the endoscope system ofthe present invention;

FIGS. 17(a)-17(c) show the spectral intensities of the blue, green, andred light, respectively, that has been reflected from living tissue andthe fluorescent light emitted by the fluorescent labels (shown in FIGS.11(a)-11(d)) when the light reaches the light receiving surface of thedetector 36 (FIG. 1) after having been transmitted through the tunablefilter 35;

FIG. 17(d) shows the manner that plural fluorescent wavelengths in theinfrared range are detected by scanning the transmission band passwavelength of a tunable filter;

FIGS. 18(a)-18(d) relate to an exemplary design of a two-layer, tunableFabry-Perot etalon filter, with FIG. 18(a) showing the spectraltransmittance of a semi-transmitting coating deposited on the substratesurface that forms an air gap, and FIGS. 18(b)-18(d) showing thespectral transmittances of the tunable filter when the air gap distanced (shown in FIG. 12) is 375 nm, 500 nm, and 625 nm, respectively;

FIGS. 19(a)-19(d) relate to an exemplary design of the three-layer,tunable Fabry-Perot etalon filter wherein the wavelength λ offluorescent light emitted by the fluorescent labels is in the range950≦λ≦1050 nm;

FIGS. 20(a)-20(c) show the spectral transmittances of the translucentcoatings on the surfaces of the first through third substrates of anexemplary three-layer, tunable Fabry-Perot etalon filter, respectively,that face the translucent film;

FIGS. 20(d)-20(f) show the spectral transmittances of the three-layer,tunable Fabry-Perot etalon filter when the wavelength λ of fluorescentlight emitted by the fluorescent labels is in the range 950≦λ≦1050 nm;

FIGS. 21(a)-21(c) show exemplary structures of tunable filters that maybe provided for use with an objective lens 33, with FIG. 21(a) having atwo-layer, tunable Fabry-Perot etalon filter, with FIG. 21(b) having athree-layer, tunable Fabry-Perot etalon filter, and with FIG. 21(c)having two, two-layer, tunable Fabry-Perot etalon filters;

FIG. 22 is a timing chart for use in explaining the operation of theendoscope of the present invention for color image observation;

FIG. 23 is a timing chart for use in explaining the operation of theendoscope of the present invention for fluorescence detection and colorimage observation;

FIG. 24 shows a timing chart wherein more than three differentfluorescent light emitting substances are to be separately detected;

FIG. 25 is a timing chart for use in explaining the operation of theendoscope of the present invention for fluorescence detection and colorimage observation based on another operation principle;

FIG. 26 shows a display image on a monitor;

FIGS. 27 and 28 show another embodiment of the rotational disk of thelight source optical system and with three different band pass filtersattached to the windows 29 d, 29 e, and 29 f, respectively, of therotational disk, with FIG. 27 showing the structure of a rotational disk23 b and FIG. 28 showing the spectral transmittances of the threedifferent band pass filters B, G, R;

FIGS. 29(a)-29(c) show the spectral transmittances of another embodimentof a tunable filter, with FIG. 29(a) being the spectral transmittance ofa semi-transmitting coating that is deposited on the substrates thatform an air gap, with FIG. 29(b) being the spectral transmittance of thetunable filter having an air gap, and with FIG. 29(c) being the spectraltransmittance of the tunable filter when the air gap distance is changedto a different distance;

FIGS. 30(a)-30(d) show the spectral intensity of light that istransmitted through the tunable filter 35 and reaches the lightreceiving surface of the detector 36;

FIGS. 31(a)-31(c) show the spectral transmittances of an exemplarytwo-layer, tunable filter when the air gap distance d is 1800 nm, 2000nm, and 2200 nm, respectively;

FIGS. 32(a)-32(c) show the spectral transmittances of an exemplarythree-layer, tunable filter, with FIG. 32(a) showing the spectraltransmittance when d₁=d₂=900 nm, with FIG. 32(b) showing the spectraltransmittance when d, =d₂=1000 nm, and with FIG. 32(c) showing thespectral transmittance when d₁=d₂=1100 nm;

FIG. 33 shows the structure of a charge multiplying, solid-state imagepickup element;

FIG. 34 is a timing chart that illustrates the relative timing of asensitivity control pulse CMD (Charge Multiplying Detector) and ofhorizontal transfer pulses S1 and S2 used with the solid-state imagepickup element shown in FIG. 33;

FIG. 35 shows the sensitivity (i.e., the multiplication factor) of thecharge multiplying solid-state image pickup element versus the appliedvoltage to the solid-state image pickup element shown in FIG. 33;

FIG. 36 is a timing chart for driving the charge multiplying,solid-state image pickup element shown in FIG. 33;

FIG. 37 is a prior art illustration to show an example of a quantum dot;

FIG. 38 is a graphical representation to show the excitation andemission spectra of the quantum dot shown in FIG. 37;

FIG. 39 is a block diagram to show an alternative configuration in partof another embodiment of the present invention;

FIG. 40 shows the overall structure of another embodiment of anendoscope system according to the present invention, wherein the opticalelements for separating and detecting plural fluorescent light sourcesare located within a separate housing that receives light from theendoscope tip of an endoscope that uses an optical fiber bundle in itsobservation optics (such a combination is sometimes termed a‘fiberscope’);

FIG. 41 illustrates a minor change from that illustrated in FIG. 40;

FIG. 42 also illustrates a minor modification from FIG. 40;

FIG. 43 illustrates another embodiment of the present invention;

FIG. 44 illustrates an additional embodiment of the present invention;

FIG. 45 illustrates the spectral transmittance of an infraredtransmitting filter that is used for detecting only fluorescentwavelengths;

FIGS. 46 and 47 show another embodiment of the present invention thatuses a capsule endoscope that functions similarly to the endoscope shownin FIG. 1, but outputs its data wirelessly, with FIG. 46 being a sidesectional view and FIG. 47 being a front view;

FIGS. 48(a) shows the spectral transmittance of an excitation lightcut-off filter 34;

FIGS. 48(b)-48(d) show the overall spectral transmittances of the sameexcitation light cut-off filter when combined with the tunable filtershaving individual spectral transmittances as shown in FIGS. 18(b)-18(d);and

FIGS. 49(a)-49(d) show the spectral transmittances relating to atwo-layer, tunable Fabry-Perot etalon filter.

DETAILED DESCRIPTION

The endoscope system according to the present invention may be used forendoscopic diagnosis of a subject who has been administered plural knownfluorescent labels that produce fluorescent light in the near-infraredrange, and is characterized by having: an illumination system thatincludes multiple wavelengths λ in the wavelength range 600 nm≦λ≦2000 nmso as to excite different fluorescent labels; a detection system thatincludes a wavelength separation element for separating fluorescentwavelengths produced by the fluorescent labels; and a controller thatcontrols the wavelength separation element so as to scan for peakwavelengths of the fluorescence produced by the fluorescent labels.

The endoscope system shown in FIG. 1 is characterized in that itprovides components within the endoscope tip for separating andtransmitting plural fluorescent wavelengths so as to enable observationsand diagnoses of lesions, such as cancers, using light in thenear-infrared range. The wavelength range used is approximately 600-2000nm, as these wavelengths are not significantly scattered or absorbedwhen living tissue is illuminated with such wavelengths, and thus thesewavelengths reach deep into living tissue and enable a more effectivediagnosis of cancer within a living body. A wavelength separationelement is controlled so as to scan for the fluorescent emission peaksproduced by the fluorescent labels. Such a technique enables high speedseparation of fluorescent peak emission wavelengths in the near-infraredrange. FIG. 2 shows in greater detail the structure of the light sourceoptical system 2 shown in FIG. 1.

According to a second type of the endoscope system of the presentinvention, an endoscope system is provided for endoscopic diagnosis of asubject who has previously been administered plural, known fluorescentlight emitting labels that produce different fluorescent light emissionsin the near-infrared range. The endoscope includes an illuminationsystem for illuminating the subject with wavelengths that includewavelengths in the range 600-2000 nm so as to provide excitation lightfor the fluorescent labels, a detection system that includes awavelength separation element for separating the fluorescent lightemissions by the different fluorescent substances that comprise thelabels, and a controller that controls the wavelength separation elementso as to scan for the peak wavelengths of the fluorescent emissionsproduced by the fluorescent labels, with the detection system andcontroller being provided in an ocular portion (i.e., the eyepieceportion) of the endoscope.

In the first and second types of the endoscope system of the presentinvention discussed above, the illumination system includes a lightsource that is detachably provided with plural wavelength selectivefilters that are switched into and out of the light path in order toselect at least the following two illumination modes:

-   -   illumination mode 1—wherein light is emitted only in the visible        wavelength range, and    -   illumination mode 2—wherein light is emitted having a wavelength        component λ in the range 600≦λ≦2000 nm.

It is desirable that the voltage for driving the wavelength separationelement is changed only during the illumination mode 2.

In the first and second types of the endoscope system of the presentinvention as discussed above, it is desirable that a voltage for drivingthe wavelength separation element is changed n times for n differentfluorescent labels. In this way, at least two fluorescent wavelengthscan be separated for observation.

The third type of the endoscope system of the present invention is anendoscope system for endoscopic diagnosis of a subject who has beenadministered plural known fluorescent labels that, when excited, producefluorescence in the near-infrared range, characterized by the following:an illumination system for illuminating the subject with at least partof the wavelength range 600-2000 nm including at least part of theexcitation wavelengths of the fluorescent labels, a detection systemincluding a wavelength separation element for separating fluorescentwavelengths produced by the plural fluorescent labels, and pluraldetection elements for detecting individual fluorescent wavelengthsseparated by the wavelength separation element, wherein the detectionsystem and the plural detection elements are provided at the tip of theendoscope.

The third type of the endoscope system of the present inventionseparates fluorescent wavelengths without any control of the wavelengthseparation element, which simplifies the structure of the endoscopesystem.

The fourth type of the endoscope system of the present invention is forendoscopic diagnosis of a subject administered plural known fluorescentlabels producing fluorescence in the near-infrared range, characterizedby the following: an illumination system for illuminating the subjectwith at least part of the wavelength range 600-2000 nm including atleast part of the excitation light wavelengths of the fluorescentlabels, a detection system and including a wavelength separation elementfor separating fluorescent wavelengths produced by the pluralfluorescent labels, and plural detection elements for detectingindividual fluorescent wavelengths separated by the wavelengthseparation element wherein the detection system and the plural detectionelements are provided in the eyepiece of the endoscope.

The fourth type of the endoscope system of the present inventionpositions the detection system and plural detection elements at theendoscope eyepiece, which enables the distal end of the endoscope to bethin.

It is desirable in the second and fourth types of the endoscope systemof the present invention that an objective optical system be provided atthe endoscope tip, that the objective optical system has at least onefilter, and a cut-off filter that blocks the excitation lightwavelengths of the fluorescent labels. In such a case, visible andinfrared components can be transmitted.

In the third and fourth types of the endoscope system of the presentinvention, the illumination system includes a light source. The lightsource is detachably provided with a filter that selectively transmitsor reflects at least part of the wavelength range 600-2000 nm. Thewavelength separation element separates plural fluorescent wavelengthsindividually when the filter is inserted. Furthermore, it is desirablein the third and fourth types of the endoscope system of the presentinvention that the wavelength separation element has an ability toseparate at least three fluorescent wavelengths.

In the first through fourth types of the endoscope system of the presentinvention, the detection system is further provided with at least onefilter which cuts off the wavelengths that excite the fluorescent labelsbut enables visible and infrared wavelengths of interest to betransmitted.

The first through fourth types of the endoscope system of the presentinvention further include an image processing device for merging afluorescent image and a visible light observation image of the subject,and a monitor for displaying the merged image. The display of a mergedfluorescent and visible light observation image allows the simultaneousobservation of a fluorescent image and an ordinary observation image.Hence, the fluorescent image and ordinary observation image are obtainedwith no time lag, enabling the locating of the lesion in a simple andhighly accurate manner.

It is desirable in the first and second types of the endoscope system ofthe present invention that the fluorescent labels be substancescontaining InAs nanocrystal. The wavelength separation element of thefirst through fourth embodiments of the endoscope system of the presentinvention is preferably an etalon. Using an etalon as a variablespectral transmittance element ensures that the fluorescent wavelengthsproduced by fluorescent labels are detected even if they have a Gaussiandistribution in a narrow wavelength region.

It is desirable that the wavelength separation element consists of atunable Fabry-Perot etalon filter comprising three or more alignedtranslucent substrates. Using three or more aligned translucentsubstrates enables the separation of fluorescent emissions having atleast two wavelength peaks. However, the tunable Fabry-Perot etalonfilter may be composed of only two aligned translucent substrates.

The present invention provides an endoscope system for observation anddiagnosis of living tissue within a subject who has previously beenadministered plural fluorescent labels that emit different fluorescentwavelengths as a result, for example, of being formed of differentmaterials.

It is desirable that the respective fluorescent labels have narrowfluorescent wavelength properties so that plural fluorescent labels canbe introduced so as to increase the number of types of cancer-specificproteins detected for improved accuracy of diagnosis. Quantum dots (Qdots) can be used as the labels described above.

FIG. 37 is an illustration to show an example of a quantum dot. In FIG.37, a quantum dot 80 has, for example, a semiconductor micro sphereformed of CdSe having a diameter of 2-5 nm as a nucleus, which is coatedwith ZnS in order to form a shell layer. Hydroxyl groups are attached tothe shell layer via a sulfur molecule and thus proteins that target partof the hydroxyl group become bonded to the quantum dot.

FIG. 38 shows the excitation light spectrum and the emission spectrum ofa quantum dot. In FIG. 38, the broken line is the spectral distributionof the excitation light for a quantum dot and the solid line is thespectral distribution of the light emitted by a quantum dot that isformed of CdSe and InP. In order to distinguish different types ofquantum dots, the quantum dots may have different particle sizes. Asshown in FIG. 38, the excitation light wavelength distribution reachesto 700 nm. The quantum dot emits fluorescence in the near-infraredwavelength range. Quantum dots have the following characteristicfluorescent wavelength emission characteristics as compared to the priorart fluorescent dyes:

-   -   (1) the full band width of the emission spectrum profile of a        quantum dot as measured at 50% of the peak intensity is about        1/200^(th) of the central wavelength of the spectrum (typically        20-30 nm) and is only about one-third that of a fluorescent dye;    -   (2) the peak wavelengths of the emission spectrum can be        relatively flexibly selected in the range of approximately        400-2000 nm depending on the size (diameter) and material of the        quantum dot, so as to create different, narrow-wavelength,        Gaussian distributions; and    -   (3) the excitation light spectrum is intensified at the shorter        wavelengths within the visible to ultraviolet range regardless        of the center wavelength of the emission spectrum.

When used for the detection of a single molecule, the quantum dots havethe following advantages over conventional fluorescent dyes:

-   -   (1) they are very small in size and do not interfere with the        movement of target molecules;    -   (2) their emission efficiency is much higher than that of        conventional fluorescent dyes and thus, they allow highly        sensitive detection of a single molecule; and    -   (3) they are rarely discolored after an extended period of        excitation.

According to these advantages, it is suitable to use fluorescent labelshaving the properties provided by quantum dots when conducting a singlemolecule detection analysis.

The quantum dots characteristically allow for relative flexibility inthe selection of plural emission center wavelengths, depending on theirparticle size and the material used, and they have a narrow half bandwidth emission spectrum. Thus, more types of molecules can be identifiedin a given usable wavelength range as compared with using conventionalfluorescent dyes. Furthermore, quantum dots have a wider excitationlight spectrum. Hence, plural different quantum dots can be excited atonce using light in the visible and infrared range.

FIG. 1 shows the entire structure of a first embodiment of the endoscopesystem according to the present invention. In FIG. 1, an endoscopesystem 1 is formed of a light source system 2, an endoscope 3, aprocessor 5, and a monitor 6. This embodiment is characterized by havinga structure that separates and detects plural fluorescent wavelengthswithin the endoscope tip.

FIG. 2 is an illustration that shows the structure of the light sourceoptical system in the light source system 2 which can be used to detectfluorescent labels such as quantum dots (having, for example, emissionspectra as shown in FIG. 38) that have previously been introduced intoliving tissue 4 to be examined with the endoscope system of the presentinvention. The light source optical system 2 is formed of a light source21, a turret 22 provided with plural optical filters, and a rotationaldisk 23 provided with plural optical filters that are arrangedconcentrically. The light source 21 can be a Xenon lamp that includeslight wavelengths in the visible range as well as in the excitationlight wavelength range of the fluorescent labels.

FIG. 3 is an end view of the turret 22 shown in FIG. 2. The turret isprovided with two different band pass filters. The respective band passfilters have, for example, the spectral transmittances shown in FIG. 4.

FIG. 4 shows the spectral transmittance of a band pass filter 27 a thattransmits primarily visible light (solid line) and of a band pass filter27 b that transmits primarily near-infrared light (the dot-dash line).The turret 22 is rotated (as shown by the curved arrow R in FIG. 2)around the rotation axis 25 so as to insert one of the band pass filtersinto the optical path. The turret 22 is further provided with amechanism (not shown) that moves the turret 22 in a direction orthogonalto the optical axis CL of the light source optical system.

FIG. 5 shows a layout of windows that are provided on the rotationaldisk 23 around the rotation axis 26. The windows are providedconcentrically spaced on the outer and inner regions of the disk.Optical filters are bonded and fixed to inner region windows 29 a, 29 b,and 29 c, respectively. The rotational disk 23 is rotated around therotation axis 26 at a fixed rotation speed. The rotational disk 23 isalso moved by a rotational disk moving mechanism (not shown) so as tomove the rotational disk 23 in a direction that is orthogonal to theoptical axis CL of the light source optical system 2 (as shown by thedouble-headed arrow S).

After being moved by the rotational disk moving mechanism to a properposition, the rotational disk 23 can selectively create pluralillumination modes. Table 1 below lists the illumination modes availableusing the light source optical system of this embodiment. A modeselection mechanism (not shown) is used to automatically select a givencombination of the optical filter in the turret 22 and the window regionformed in the rotational disk 23, as detailed in Table 1 below. TABLE 1Turret 22 Rotational Disk 23 illumination light visible light mode: 27a29a, 29b, 29c visible light (B, G, R) infrared mode: 27b 28a, 28b, 28cinfrared (excitation light)

FIG. 6 shows exemplary spectral transmittances of the optical filtersattached to the inner windows of the rotational disk 23, with the bandpass filter for transmitting blue light (B) being illustrated by a solidline, the band pass filter for transmitting green light (G) beingillustrated by a dot-dash line, and the band pass filter fortransmitting red light (R) being illustrated by a dash-dash line. Whenthe turret 22 is rotated so as to insert the band pass filter 27 a intothe optical path, the rotational disk 23 is operated to sequentiallyinsert the inner windows 29 a, 29 b, and 29 c into the optical path soas to realize field sequential color illumination suitable for theendoscope system.

FIG. 7 shows a manner of illumination by the illumination system. Amongthe light emitted from the light source 21, light mainly in the visibleregion having wavelengths λ in the range 400≦λ≦650 nm is selectivelytransmitted through the band pass filter 27 a (not shown) and separatedby the rotational disk into light of the blue B wavelength range, lightof the green G wavelength range, and light of the red R wavelengthrange. Consequently, the three light colors R, G, and B are repeatedlyand intermittently emitted. When the turret 22 is rotated so as toinsert the band pass filter 27 b into the optical path, the rotationaldisk 23 is operated so as to sequentially insert the outer windows 28 a,28 b, and 28 c into the optical path.

In this case, among the light emitted from the light source 21, lightmainly in the near-infrared range is selectively transmitted through theband pass filter 27 b, and then is repeatedly and intermittentlytransmitted by the rotational disk 23. Other, non-intermittent,illumination can be achieved by stopping the rotation of the rotationaldisk so as to keep any single window 28 a, 28 b, or 28 c in the opticalpath, or by retracting the rotational disk from the optical path. Asshown in FIG. 1, the illumination lens 32, the light guide fiber 31 aswell as the reflected light receiving optics may be provided within theendoscope tip. Light produced by the light source 21 is transferred bythe light guide fiber 31 so as to illuminate the living tissue 4 throughthe illumination lens 32.

FIGS. 8(a)-8(d) show exemplary spectral intensity distributions of lightilluminating the living tissue 4. More specifically, FIGS. 8(a)-8(c)show the spectral intensities in arbitrary units (A.U.) of light thatsequentially illuminates the living tissue while the visible light modeis selected, and FIG. 8(d) shows the spectral intensity in arbitraryunits (A.U.) of light that illuminates the living tissue while theinfrared mode is selected.

FIG. 9 shows the spectral reflectance for normal living tissue. In FIG.9 the reflection intensity is plotted on the ordinate in arbitrary units(A.U.) and the wavelength (in nm) is plotted on the abscissa. Light inthe red and infrared ranges is reflected and/or absorbed less by livingtissue and thus reaches deep inside the living tissue as compared withthe other visible light. Thus, light in the red and infrared ranges canexcite the fluorescent labels wherever they are located within theliving tissue, (i.e., on the surface or deep inside) and thus makes aproper excitation light. Taking into account the properties of thefluorescent labels, the excitation light can have a wavelength λanywhere in the range 600≦λ≦2000 nm.

As shown in FIG. 1, an objective lens 33 is provided at the endoscopetip, adjacent to the illumination lens 32. The light receiving surfaceof a detector 36, such as a CCD, CMOS or another highly sensitive imagepickup element, is provided at the image plane of the objective lens 33.An excitation light cut-off filter 34 having a fixed transmittance and atunable filter 35 having a variable transmittance are provided betweenthe objective lens 33 and the detector 36. A stop 37 is providedimmediately following the objective lens 33.

FIG. 10 shows the percentage spectral transmittance of the excitationlight cut-off filter 34. The excitation light cut-off filter 34transmits visible light and the light in the fluorescent wavelengthrange of the fluorescent labels, and cuts off the light in thenear-infrared range that excites the fluorescent labels. In most cases,the intensity of the fluorescence produced by the fluorescent labels issignificantly low, less than 1/1000, in comparison with the intensity ofthe excitation light. Thus, it is desirable that the excitation lightcut-off filter 34 has a cut-off performance of OD4 or more, where ODstands for Optical Density and “OD4 or more” means that log₁₀ (I/I′)≧4,where I is the intensity of light entering the filter, and I′ is theintensity of light transmitted by the filter.

Providing a filter having such a cut-off performance prevents theexcitation light from reaching the light receiving surface of thedetector, and thus allows the detection of only the fluorescence so asto provide good contrast. It is desirable that the excitation lightcut-off filter 34 be provided on the object side of the tunable filter35. In this way, the excitation light that is reflected by the livingtissue 4 is prevented from causing the tunable filter 35 to produceself-fluorescence, which can be a source of noise in the detectionoperation.

FIGS. 11(a)-11(d) show the spectral intensities in arbitrary units(A.U.) of light entering the objective lens 33 from the living tissuewhen the illumination light shown in FIGS. 8(a)-8(d) is irradiated ontoliving tissue that has had fluorescent labels introduced. The lightentering the objective lens 33 includes two different components,namely, the light reflected by the living tissue (hereafter simplytermed “reflected light”, the intensity of which is shown by solidlines) and the fluorescence produced by the fluorescent labels (shownusing dash-dash lines). In FIGS. 11(a)-11(d), although the spectralintensity curves of the reflected light and of the fluorescence are bothshown in each figure, the intensity of the fluorescence has been greatlyexaggerated for convenience of illustration. More particularly, FIGS.11(a)-11(c) show the spectral intensities of light entering theobjective lens 33 from the living tissue while the visible light mode isselected. The fluorescent labels can be excited by light in the visiblerange. Thus, in addition to the reflected light, fluorescence enters theobjective lens 33. For example, when the blue illumination light isirradiated, as shown in FIG. 11(a), the reflected light carryinginformation from on and near the surface of the living tissue and thefluorescence from the fluorescent labels distributed on and near thesurface layer of the living tissue enter the objective lens 33.Likewise, when green illumination light is irradiated, as shown in FIG.11(b), the reflected light carrying information from the surface to amiddle layer of the living tissue and the fluorescence from thefluorescent labels distributed from the surface to the middle layer ofthe living tissue enter the objective lens 33.

In addition to the fluorescence shown, the blue and green light inducesself-fluorescence of the living tissue and the green to red light entersthe objective lens 33. These light components are not shown in thefigures. When the red illumination light is irradiated, as shown in FIG.11(c), the reflected light carrying information from the surface to arelatively deep layer of the living tissue and the fluorescence from thefluorescent labels distributed from the surface to a relatively deeplayer of the living tissue enter the objective lens 33.

FIG. 11(d) shows the spectral intensity of light entering the objectivelens 33 from the living tissue while the infrared mode is selected. Whenthe illumination light in the red and near-infrared range having arelatively wide range of wavelengths λ in the range 620≦λ≦830 nm isirradiated, the reflected light carrying information on the deep layerof the living tissue and the fluorescence from the fluorescent labelsdistributed from the surface to a relatively deep layer of the livingtissue all enter the objective lens 33.

The tunable filter that is used in this embodiment is a band pass filterof the tunable Fabry-Perot etalon type and has a transmittancewavelength range that may be varied. For example, the operation andstructure of a two-layer, tunable Fabry-Perot etalon filter will now bedescribed. FIG. 12 shows the structure of such a tunable filter and FIG.13 shows the spectral transmittance of such a tunable filter.

As shown in FIG. 12, the tunable band pass filter is formed of twosubstrates 35X-1 and 35X-2, on the facing surfaces of which reflectivecoatings 35Y-1 and 35Y-2 are formed with an air gap d in-between. Lightentering the substrate 35X-1 is subject to multiple reflections. The airgap distance d is changed so as to modify the peak wavelengthtransmittance that emerges from the substrate 35X-2. In other words,when the air gap distance d shown in FIG. 12 is changed, the wavelengthof the maximum transmittance is changed from Ta to Tb, as shown in FIG.13. The air gap distance d can be changed using a Piezo-electricelement. The substrates can be made of transparent film and each has thesame reflective property as either of the reflective coatings 35Y-1 and35Y-2.

The term ‘reflective coating’ as used herein means a coating thatexhibits a high reflectance (and thus low transmittance) to a range ofwavelengths that includes the near-infrared range. Such a reflectivecoating can be formed of multiple laminated metal coatings (such asdeposited silver) or from several to a score or more of laminateddielectric coatings. The tunable filter 35 that is provided between theobjective lens 33 and detector 36 can distinguish among the differentfluorescent labels by detecting specific ranges of wavelengths. The airgap distance is controlled in order to scan for the peak wavelengths oflight transmitted through the tunable filter so that plural wavelengthsin the near-infrared range can be separated for detection.

The operation and structure of a three-layer, tunable Fabry-Perot etalonfilter 35 will now be described. FIG. 14 shows a cross section of such atunable band pass filter. In FIG. 14, glass substrates 35X-1, 35X-2, and35X-3 have reflective coatings 35 a, 35 b, 35 c, and 35 e deposited ontheir facing surfaces. The reflective coatings 35 a, 35 b, 35 c, and 35e are each formed of laminated metal coatings of, for example, depositedsilver, or they may each be formed of several to as many as a score ormore of laminated dielectric coatings.

FIG. 14 further shows air gaps d₁ and d₂, cylindrical laminatedpiezoelectric actuator elements 71, 71 fixed to the peripheries of theglass substrates 35X-1, 35X-2 and 35X-3, reflective coatings 35 a, 35 b,35 c, and 35 e, and variable voltage power sources 70, 70 for applyingvoltage to the laminated piezoelectric actuator elements 71, 71. Thelaminated piezoelectric actuator elements 71, 71 expand or contract intheir axial direction (i.e., the horizontal direction of FIG. 14) ininverse proportion to the applied voltage so as to change the air gapdistances d₁ and d₂ in a known manner. The top and bottom actuatorelements 71, 71 in FIG. 14 independently control the air gaps d₁ and d₂.

The excitation light blocking property of the excitation light cut-offfilter 34 can also be applied to the tunable filter 35. For example, anexcitation light blocking (i.e., cut-off) coating can be applied to thesubstrate 35X-1 on the surface that is opposite the reflective coating35 a so that the excitation light cut-off filter 34 can be eliminated,thus saving space between the objective lens 33 and the detector 36.

FIG. 15 shows a cross section of another three-layer, tunableFabry-Perot etalon filter in which the substrates are made oftranslucent film. This leads to reducing the weight, thus reducing theload of the air gap control devices such as the piezoelectric elements.This also contributes to higher response speeds and in saving power. Thetunable Fabry-Perot etalon filter may be formed of plural layers thatare constructed of substrates and reflective coatings, formed of onlytranslucent films, or formed of a combination of these components so asto achieve a desired effect.

The endoscope system of the present invention guides the endoscope tipto a subject (living tissue) and enables color image observation of thesubject using illumination light in the visible range. Thus, the tunablefilter has to transmit the light in the visible range and scan for thefluorescence produced by the plural fluorescent labels in thenear-infrared range.

The spectral transmittance required of a three-layer tunable filter thatmay be used in the endoscope system of the present invention will now bedescribed with reference to FIGS. 16(a)-16(c). It is assumed here thatthe wavelengths of fluorescence from the fluorescent labels is in therange 900-1100 nm.

FIG. 16(a) shows an exemplary spectral transmittance of thesemi-transmitting coating deposited on the substrate forming an air gap.In this example, the coating exhibits a much reduced transmittance tothe wavelengths λ in the range 900 nm≦λ≦1100 nm than to otherwavelengths.

FIG. 16(b) shows the spectral transmittance of a tunable filter havingan air gap distance A, with the light being subject to multipleinterferences. As a result of multiple interferences of the light raysin the air gap, significantly narrow band pass regions occur in therange 900-1100 nm so as to enable the discerning of fluorescentemissions from the plural fluorescent labels. On the other hand, beingscarcely subject to multiple interferences, light in the visible rangeis transmitted.

FIG. 16(c) shows the spectral transmittance of a tunable filter havingan air gap distance B. Light is also subject to multiple interferenceswhen the air gap distance is the distance B. The transmittance range isshifted according to the air gap distance within the range 900-1100 nm.However, no transmittance changes are observed for light in the visiblerange. The air gap distance can be changed to modify the transmittanceof a desired range of wavelength and to maintain the transmittance ofother wavelengths. To this end, the spectral transmittance of thesemi-transmitting coating deposited on the substrate forming an air gapshould be properly defined. It is desirable to use semi-transmittingcoatings made of dielectric multi-layered coatings for obtaining thespectral transmittance described above.

FIGS. 17(a)-17(d) show the spectral intensities of the reflected lightfrom the living tissue and the fluorescence from the fluorescent labelsshown in FIGS. 11(a)-11(d) after the light has reached the lightreceiving surface of the detector 36 (i.e., after having beentransmitted through the tunable filter 35 with a spectral transmittanceas shown in FIGS. 16(a)-16(c)). In FIGS. 17(a)-17(d), the intensity isplotted on the ordinate in arbitrary units (A.U.) and the wavelength isplotted on the abscissa in units of nm. Once again, in FIGS.17(a)-17(d), although the spectral intensity curves of the reflectedlight and of the fluorescence are both shown in each figure, theintensity of the fluorescence has been greatly exaggerated forconvenience of illustration.

The tunable filter 35 transmits light in the visible range regardless ofthe air gap distance. Light in the blue (B), green (G) and red (R)wavelength ranges (as shown in FIGS. 17(a)-17(c), respectively) that isreflected from the living tissue always reaches the light receivingsurface of the detector 36. On the other hand, among the lightwavelengths in the range 900-1100 nm, light in a wavelength range havinga peak near 1000 nm reaches the light receiving surface of the detector36 when the air gap distance is the distance ‘A’.

The fluorescence, because it has a significantly lower intensity thanthe reflected light, can be neglected in the R, G, B color imageobservation. Among the light entering the objective lens 33 from theliving tissue while the infrared mode is selected, light in thenear-infrared range that excites the fluorescent labels is cut off bythe excitation light cut-off filter 34. As shown in FIG. 17(d), only thefluorescence reaches the light receiving surface of the detector 36. Theair gap distance may be varied between the positions ‘A’ and ‘B’ so asto repeatedly scan the peak wavelengths in the direction indicated bythe arrows. In this way, plural fluorescent wavelengths in the infraredrange can be detected.

FIGS. 18(a)-18(d) show the spectral transmittances relating to atwo-layer, tunable Fabry-Perot etalon filter that is designed for whenthe fluorescent emission wavelength peaks are in the wavelength range of950-1050 nm. FIG. 18(a) shows the spectral transmittance of asemi-transmitting coating deposited on the substrate surfaces that forman air gap. In this case, the spectral transmittance of thesemi-transmitting coating satisfies the following conditions:T1≧80%  Condition (1)T2≦20%  Condition (2)where

-   -   T1 is the average transmittance in the wavelength region of 400        nm≦λ≦650 nm, and    -   T2 is a transmittance in a wavelength band having a lower        boundary that is 50 nm shorter than the peak transmittance        wavelength of the shortest fluorescence wavelength, and an upper        boundary that is 50 nm longer than the peak transmittance        wavelength of the longest fluorescence wavelength.

FIGS. 18(b)-18(d) show the spectral transmittances of the tunable filterwhen the air gap distance d is 375 nm, 500 nm, and 625 nm, respectively.A transmission range having a half band width of only 15 nm isestablished within the wavelength range 900-1100 nm, and an averagetransmittance of 70% or more is ensured for the visible range. FIG.18(b) shows the spectral transmittance of the tunable filter with d=375nm. In this case, the transmission wavelength peak is at 950 nm, and thetransmittance is 3% or less in the approximate ranges 900-930 nm and970-1100 nm.

FIG. 18(c) shows the spectral transmittance of the tunable filter withd=500 nm. In this case, there is a narrow band width transmission peakat λ=1000 nm. The transmittance is 3% or less in the wavelength ranges900-980 nm and 1020-1100 nm. FIG. 18(d) shows the spectral transmittanceof the tunable filter with d=625 nm. In this case, the transmissionwavelengths have a peak at 1050 nm, and the transmittance is 3% or lessin the wavelength ranges 900-1030 nm and 1070-1100 nm.

An appropriate spectral transmittance of the tunable filter forseparating plural fluorescent wavelengths for detection can be obtainedby setting the transmittance of the semi-transmitting coating to be 20%or less in the wavelength range extended by at least 50 nm with respectto the range defined by the shortest fluorescent wavelength peak and thelongest fluorescent wavelength peak used. The air gap d is fixed at anappropriate distance for RGB color image observation.

FIGS. 49(a)-49(d) show the spectral transmittances relating to atwo-layer, tunable Fabry-Perot etalon filter that is designed for whenthe fluorescent emission wavelength peaks are in the wavelength range of950-1050 nm and that has different transmittance properties from thoseshown in FIGS. 18(a)-18(d). FIG. 49(a) shows the spectral transmittanceof a semi-transmitting coating deposited on the substrate surfaces thatform an air gap. In this case, the spectral transmittance of thesemi-transmitting coating satisfies the following conditions:T1≧80%  Condition (1)T2≦35%  Condition (2′)where

-   -   T1 is the average transmittance in the wavelength region of 400        nm≦λ≦650 nm, and    -   T2 is a transmittance in the wavelength band having a lower        boundary that is 50 nm shorter than the peak transmittance        wavelength of the shortest fluorescence wavelength, and an upper        boundary that is 50 nm longer than the peak transmittance        wavelength of the longest fluorescence wavelength.

FIGS. 49(b)-49(d) show the spectral transmittances of the tunable filterwhen the air gap distance d is 925 nm, 1000 nm, and 1075 nm,respectively. A transmission range having a half band width of only 30nm is established within the wavelength range 900-1100 nm, and anaverage transmittance of 70% or more is ensured for the visible range.FIG. 49(b) shows the spectral transmittance of the tunable filter withd=925 nm. In this case, the transmission wavelength peak is at 950 nm.

FIG. 49(c) shows the spectral transmittance of the tunable filter withd=1000 nm. In this case, there is a narrow band width transmission peakat λ=1000 nm. FIG. 49(d) shows the spectral transmittance of the tunablefilter with d=1075 nm. In this case, the transmission wavelengths have apeak at 1050 nm.

The tunable filter having a transmittance property mentioned above has awider half band width than the tunable filter having the transmittanceproperty shown in FIGS. 18(a)-18(d), in the wavelength region of 900nm-1100 nm. This causes the amount of flourescent light passing throughthe tunable filter to increase and serves to achieve both separation ofthe plural fluorescent lights and detection of the brighter flourescentimages.

FIG. 48(a) shows the spectral transmittance properties of the excitationlight cut-off filter 34. Here the excitation light has a band widthranging from 720 nm to 850 nm which is determined by the half band widthof the excitation light used in the light source system. FIG. 48(a)shows the spectral transmittance properties of the excitation lightcut-off filter 34. FIGS. 48(b)-48(d) show the total spectraltransmittance properties of the excitation light cut-off filter 34 whencombined with the tunable filters having individual spectraltransmittances as shown in FIGS. 18(b)-18(d).

The excitation light cut-off filter 34 of this embodiment satisfies thefollowing Conditions (3)-(5):T_(Ex1)≧90%  Condition (3)T_(Ex2)≦0.01%  Condition (4)T_(Ex3)≧90%  Condition (5)where

-   -   T_(Ex1) is the average transmittance for 400 nm≦λ≦650 nm,    -   T_(Ex2) is the average transmittance for 700 nm≦λ≦870 nm,    -   T_(Ex3) is the average transmittance for 900 nm≦λ≦1100 nm, and    -   λ is the wavelength of light incident onto the filter.

The excitation light cut-off filter 34 passes the wavelength band of 400nm-650 nm (in which the transmittance is T_(EX1)) that is used forobserving a visible color image composed of R, G and B color componentsamong the light reflected by the living tissue, and cuts off thewavelength band of 700 nm-870 nm (in which the transmittance is T_(EX2))that includes the excitation light of the fluorescent label materials.The wavelength band width for T_(EX2) (700 nm-870 nm) is set to coverthe extended wavelength range whose upper limit is 20 nm longer, andwhose lower limit is 20 nm shorter, than the wavelength range determinedby the filter placed in the light source system. This ensures theblocking of the excitation light that causes noise when detecting thefluorescent light. The excitation light cut-off filter 34 has atransmittance T_(EX3) in the wavelength range that includes theflourescent lights emitted from the fluorescent label materials.

The excitation light cut-off filter 34 when combined with each of thetunable filters having individual spectral transmittances as shown inFIGS. 18(b)-18(d) satisfy the following Conditions (6)-(9):T3≧60%  Condition (6)T4≦0.01%  Condition (7)T5≧65%  Condition (8) and5 nm≦d5≦35 nm  Condition (9)where

-   -   T₃ is the average transmittance within the visible wavelength        range of 400 nm≦λ≦650 nm of the illumination light,    -   T4 is the transmittance for the wavelengths within a range 20 nm        above and 20 nm below the wavelength range of the excitation        light generated by the illumination unit,    -   T5 is the transmittance at the peak transmittance wavelength for        an infrared passband in the wavelength range of 950 nm≦λ≦1050        nm,    -   d5 is the infrared passband's full width as measured at 50% of        the peak transmittance, and    -   λ is the wavelength of light incident onto the filter.

Condition (6) ensures that there is sufficient transmittance of thefilter(s) used to observe the sample in the visible region. Condition(7) ensures that the excitation light is not detected as noise duringthe detection of fluorescence emitted from the fluorescent labels byblocking wavelengths within a range 20 nm above and below the wavelengthrange of the excitation light. Conditions (8) and (9) ensure that thefluorescence wavelengths will be sufficiently transmitted by thefilter(s) used to detect the fluorescence. Thus, Conditions (6)-(9)ensure that a sufficient brightness of observation light within thevisible region is obtained while at the same time ensuring that thedetected fluorescent light from the fluorescent labels can be separatedand detected when the fluorescent labels emit fluorescence in thewavelength range 950 nm≦λ≦1050 nm.

FIGS. 19(a)-19(d) show spectral transmittances that relate to anexemplary design of a three-layer, tunable Fabry-Perot etalon filterwhen the fluorescent wavelengths of the fluorescent labels lieapproximately in the range 950-1050 nm. This exemplary design isintended to improve the resolution obtainable in the infrared region ascompared with the spectral transmittances (shown in FIGS. 18(b)-18(d))exhibited by the two-layer, tunable Fabry-Perot etalon filter discussedabove. The semi-transmitting coatings deposited on the substratesforming the air gaps of the three-layer, tunable filter have the samespectral transmittance as shown in FIG. 18(a) for the two-layer, tunablefilter.

The air gap distances can be controlled in various ways. One way is tomaintain the relationship that d₁ is equal to d₂, the other way is tomaintain the relationship that d₁ is not equal to d₂.

FIG. 19(a) shows the spectral transmittance when d, equals 375 nm and d₂equals 625 nm, which is an example that the air gap distances arecontrolled by the relation that d₁ not be equal to d₂. As can be seen inthe figure, there is a transmission peak centered at 800 nm, and thetransmittance in the wavelength range 900-1100 nm is 0.3% or less. Asone would expect, the transmittance shown for any given wavelength inFIG. 19(a) is equal to the product of the transmittances shown in FIGS.18(b) and 18(d) for that same wavelength.

FIG. 19(b) shows the spectral transmittance when both d, and d₂ equal375 nm. As one would expect in this case, the spectral transmittance atany given wavelength is the square of the transmittance at the samewavelength for the spectral transmittance curve shown in FIG. 18(b). Inthis situation, there is a transmission peak having roughly the samemaximum transmission as in FIG. 19(a), but the peak is now centered at950 nm in the wavelength range 900-1100 nm, and the half band width isreduced to about 7.5 nm. In addition, the transmittances in the ranges900-930 nm, and 970-1100 nm are each 0.1% or less.

FIG. 19(c) shows the spectral transmittance when d, equals 500 nm and d₂equals 500 nm. FIG. 19(d) shows the spectral transmittance when d,equals 625 nm and d₂ equals 625 nm. FIGS. 19(b)-19(d) are examples inwhich the air gap distances are controlled by the relation that d, equald₂. As can be seem from comparing FIGS. 19(b)-19(d), the transmissionpeak in the wavelength range 900-1100 nm, is moved to longer wavelengthsby changing the value of d, or d₂.

The two air gap distances should not be identical for good R, G, B colorimage observation. For example, FIG. 19(a) illustrates the spectraltransmittance of the tunable filter when d₁=375 nm and d₂=625 nm.

FIGS. 20(a)-20(f) show the spectral transmittances of an exemplarythree-layer, tunable Fabry-Perot etalon filter when the fluorescencesfrom the fluorescent labels lie within the approximate range of 950-1050nm. In this exemplary design, the middle substrate among the threesubstrates is made of translucent film. FIG. 20(b) shows the spectraltransmittance of the translucent film, and FIGS. 20(a) and 20(c) showthe spectral transmittances of the translucent coatings on the surfacesof the first and third substrates, respectively, that face thetranslucent film.

By using different spectral transmittances in the range 900-1100 nm, theresolution of the tunable filter in the near-infrared range can beappropriately defined. FIGS. 20(d)-20(f) show the spectraltransmittances of the tunable filter when the two air gaps have the airgap distances d₁ and d₂ as given in Table 2 below. TABLE 2 FIG. 20(d)FIG. 20(e) FIG. 20(f) d₁ (nm) 500 562.5 625 d₂ (nm) 500 625 750 peaktransmission wavelength (nm) 1000 1056 1097

In this exemplary design, the etalons having different transmittancesare independently controlled so as to realize a low transmittance forthe non-transmitting range and a larger half band width for thetransmitting wavelength range within the range 900-1100 nm. This resultsin improving the S/N ratio when fluorescent dyes having low lightemission efficiencies but larger light emission spectral width are usedas fluorescent labels.

Exemplary structures for providing the tunable filter within theendoscope optical system will now be described. FIG. 21(a) shows anexemplary structure in which a two-layer, tunable Fabry-Perot etalonfilter is provided within an objective lens 33. In FIG. 21(a), theobjective lens 33 is formed of, in order from the object side, a lens 33a, an excitation light cut-off filter 34, a biconvex lens 33 b, atunable filter 35, a doublet 33 c, and a detector 36 having a lightreceiving surface.

The tunable filter 35 includes transparent substrates 35Z-1 and 35Z-2,and translucent coatings are deposited on the surfaces thereof that forman air gap d. A piezoelectric element 72 is provided between thetransparent substrates 35Z-1 and 35Z-2. The piezoelectric element 72also serves as an aperture diaphragm.

FIG. 21(b) shows an embodiment in which a three-layer, tunableFabry-Perot etalon filter is provided in the objective lens 33 shown inFIG. 21(a). In this case, the tunable filter 35 comprises transparentsubstrates 35Z-1, 35Z-2, and 35Z-3, on the surfaces of which that formair gaps d₁ and d₂ translucent coatings are deposited. Piezoelectricelements 72 and 73 are provided between the transparent substrates 35Z-1and 35Z-2 and between the transparent substrates 35Z-2 and 35Z-3,respectively.

The piezoelectric elements 72 and 73 are independently controlled. Thepiezoelectric element 72 also serves as an aperture diaphragm. It isdesirable that the angle of incidence of light to the translucentcoating (as measured from the surface normal) not be large when thetunable filter is provided in the objective optical system as shownhere. In the figure, the angle of incidence of the axial marginal lightis less than or equal to 1°.

FIG. 21(c) shows an embodiment in which a pair of two-layer, tunableFabry-Perot etalon filters are provided in the objective lens 33. InFIG. 21(c), the objective lens 33 comprises, in order from the objectside, a concave lens 33 a, an excitation light cut-off filter 34, abiconvex lens 33 b, a tunable filter 35-1, a doublet 33 c, a tunablefilter 35-2, and a detector 36 with a light receiving surface. Thetunable filters 35-1 and 35-2 can have either the same transmittanceproperty or different transmittance properties.

Where there is not enough space to provide a three-layer, tunableFabry-Perot etalon filter in the objective optical system, a combinationof two-layer, tunable Fabry-Perot etalon filters can be used to obtainan equivalent transmittance property and an improved freedom of opticaldesign, as shown in FIG. 21(c). Furthermore, it is not necessary toprovide the tunable filter in the objective optical system when theendoscope is a fiberscope. For example, the tunable filter can insteadbe provided in the eyepiece lens or in a television camera systemconnected to the eyepiece lens. In addition, the excitation lightcut-off filter 34 can be provided immediately before the light receivingsurface of the detector 36.

FIGS. 22 and 23 are timing charts for use in explaining the operation ofthe endoscope of the present invention, with FIG. 22 being the timingchart for color image observation, and FIG. 23 being the timing chartfor fluorescence detection and color image observation. FIG. 25 is atiming chart for use in explaining the operation of the endoscope of thepresent invention for fluorescence detection and color image observationbased on another operation principle.

The operation of the endoscope for color image observation shown in FIG.22 will now be described. In the light source optical system shown inFIG. 1, the band pass filter 27 a of the turret 22 (shown in FIG. 3)that primarily transmits the visible light is inserted in the opticalpath. In this state, the inner windows 29 a, 29 b, and 29 c of therotational disk 23 shown in FIG. 5 are sequentially inserted in theoptical path so as to sequentially transmit B, G, or R lightintermittently. Here, a period of time during which the rotational disk23 rotates one time is termed one frame.

An explanation will now be provided wherein it is assumed that anobjective lens 33 as shown in FIG. 21(a) is used as the objectiveoptical system and that a two-layer, tunable Fabry-Perot etalon filterhaving the spectral transmittance as shown in FIGS. 18(b)-18(d) isprovided in the insertion section of an endoscope tip used as thetunable filter 35. It is further assumed that the air gap has a distanced=d(V₀) when a driving voltage V₀ is applied to the piezoelectricelement 72 of the tunable filter 35, and that the transmissionwavelength range of the tunable filter 35 IR(_(V0)) varies in the range950-1050 nm, depending on the air gap distance d(V₀).

It is unnecessary to scan the tunable filter 35 during color imageobservation. The driving voltage applied to the piezoelectric element 72per frame is maintained at V₀ and the air gap distance is maintained atd=d(V₀). Thus, the B, G, R light reflected by the living tissue and thefluorescence produced by the fluorescent labels reach the lightreceiving surface of the detector 36. In the timing chart, the B,G,Rlight reflected by the living tissue are indicated by RF_(B), RF_(G),and RF_(R) and the fluorescence produced by the fluorescent labels isindicated by F_(IR(V0)).

The control of the endoscope system is simplified for color imageobservation. V₀ can be changed to scan the wavelengths in accordancewith the wavelengths of the illumination light B, G, or R and thetransmittance of the tunable filter.

Light received by the detector 36 (the image pickup element) is subjectto photo-electric conversion to produce image signals for R, G, and Bcolor components, which are then supplied to a processor 5. Theprocessor 5 processes signals and displays color images of the livingtissue on a monitor 6. During the operation for color image observationshown in FIG. 22, the detector 36 receives the fluorescence along withthe reflected light. However, the intensity of the fluorescenceF_(IR(V0)) is significantly low and therefore the influence of thefluorescence on the production of color images can be neglected.

The operation of the endoscope shown in FIG. 23 is described hereafter.The endoscope used has the same structure as the one in FIG. 22. Thetiming chart in FIG. 23 shows the alternate operation of thefluorescence detection and the color image observation. In this case,the band pass filter 27 a of the turret 22 is inserted in the opticalpath during the first frame and the band pass filter 27 b is inserted inthe optical path during the following frame.

During the first frame, the rotational disk and tunable filter operateas described with reference to FIG. 22 and the detector 36 sequentiallyreceives RF_(B)+F_(IR(V0)), RF_(G)+F_(IR(V0)), RF_(R)+F_(IR(V0)). On theother hand, during the following frame, the outer windows 28 a, 28 b,and 28 c of the rotational disk 23 are sequentially inserted in theoptical path and, thus, the excitation light in the near-infrared rangeilluminates the living tissue intermittently. A driving voltage V₁ isapplied to the piezoelectric element 72 and the air gap has a distanced=d(V₁) while the window 28 a is inserted in the optical path.Consequently, the detector 36 receives F_(IR(V1)).

A driving voltage V₂ is then applied to the piezoelectric element 72 sothat the air gap has a distance d=d(V₂) while the window 28 b isinserted in the optical path. Consequently, the detector 36 receivesF_(IR(V2)). A driving voltage V₃ is then applied to the piezoelectricelement 72 so that the air gap has a distance d=d(V₃) while the window28 c is inserted in the optical path. Consequently, the detector 36receives F_(IR(V3)).

In this way, three different fluorescent wavelengths can be detected ina frame. When more than three different fluorescent wavelengths shouldbe detected, the driving voltages applied to the piezoelectric element72 can be further altered in another frame. FIG. 24 shows a timing chartin such a case. For example, driving voltages V₁-V₃ can be sequentiallyapplied to the piezoelectric element 72 while the windows 28 a-28 c arerotated sequentially into the optical path, and driving voltages V₄-V₆can be sequentially applied to the piezoelectric element 72 while thewindows 28 a-28 c are next sequentially rotated into the optical path.

The rotation cycles of the turret 22 and rotational disk 23 and thedriving voltage of the piezoelectric element 72 are controlled in asynchronous manner per frame. Control is executed by, for example, afilter control circuit 51 shown in FIG. 1. According to the timing chartin FIG. 23, color images and fluorescent information of the livingtissue can be concurrently displayed on the monitor 6 after theprocessor 5 processes the images.

FIG. 25 shows a timing chart for use in explaining the operation of theendoscope when the objective lens 33 shown in FIG. 21(b) is used as theobjective optical system provided in the endoscope tip. The tunablefilter 35 has the transmittance properties as shown in FIGS.19(b)-19(d). The differences from the timing chart in FIG. 23 will nowbe described.

Two air gaps d₁ and d₂ of the tunable filter 35 are independentlycontrolled. During the first frame, different driving voltages areapplied to the piezoelectric elements 72 and 73 so that d, does notequal d₂. Then, during the next frame, three different driving voltagesV₁, V₂ and V₃ are sequentially applied to the piezoelectric elements 72and 73 when the rotational disk has a window in the light path suchthat, at any instant during the following frame, the air gaps d₁ and d₂are identical. For example, d₁(V₁)=d₂(V₁) where d₁=d₂ so as to transmitF_(IR(V1)) while the window 28 a is in the optical path, andd₁(V₂)=d₂(V₂) where d₁=d₂ so as to transmit F_(IR(V2)) while the window28 b is in the optical path.

The method for creating images will now be described with reference toFIG. 1. A processor 5 includes a filter control circuit 51, apre-processor circuit 52, an A/D converter 53, an image signalprocessing circuit 54, and a D/A converter 55. The filter controlcircuit 51 controls the turret 22 in the light source optical system 2for positioning the band pass filters 27 a and 27 b in the optical path.It also controls the rotational disk 23 for positioning the outer andinner windows in the optical path.

The filter control circuit 51 further controls the voltage applied tothe piezoelectric elements provided in the tunable filter 35 so as tocontrol the air gap d of the tunable filter 35 and thus, shifts thetransmission wavelength range as described with reference to FIG. 13.The filter control circuit supplies the pre-processor circuit 52 withcontrol signals. The pre-processor circuit 52 adjusts the image signalssupplied from the detector 36 by adjusting the gain of an amplifier thatreceives the detected image signals and by adjusting the white balanceof color images using a white balance correction circuit.

Image signals from the pre-processor circuit 52 are supplied to the A/Dconverter 53 where analog signals are converted to digital signals. Thedigital signals converted by the A/D converter 53 are supplied to theimage signal processor circuit 54 and stored in an image memory.

Subsequently, they are subject to image processing, such as imageenhancing and noise elimination, and display controls for concurrentdisplay of a fluorescent image, a color image, and a character image.The image signal processing circuit 54 further executes the process fordisplaying a fluorescent image overlapped with a color light image orfor normalizing the fluorescent intensity by calculation between colorand fluorescent images. This provides a fluorescent image that is easyto identify along with a color image. The digital signals from the imagesignal processing circuit 54 are supplied to the D/A converter 55 wherethey are converted to analog signals. The analog signals are supplied tothe monitor 6 which displays individual images.

The filter control circuit 51 controls the transmission wavelength rangeof fluorescence so that the fluorescent peak wavelengths are calculatedor counted and the displayed image (monitor 6) is provided inpseudo-colors according to the count or counted fluorescence and theassociated fluorescent labels.

Table 3 below lists an example of the display of five differentfluorescent labels detected at a point Pi (Xi, Yi) in a lesion. TABLE 3Fluorescent Label No: 1 2 3 4 5 P₁ (X₁, Y₁): ∘ ∘ ∘ ∘ P₂ (X₂, Y₂): ∘ ∘ P₃(X₃, Y₃): ∘

The coordinate X₁, Y₁, for example, is a point on the monitor shown inFIG. 26. The fluorescent labels P₁(X₁, Y₁), P₂(X₂, Y₂), and P₃(X₃, Y₃)can be displayed in different colors. For example, P₁ can be displayedin yellow, P₂ can be displayed in red, and P₃ can be displayed in green,depending on the number and type of fluorescent labels obtained, ortheir combination. These can represent the degree of malignancy of thelesion by color, allowing a highly advanced diagnosis.

FIG. 26 shows concurrent display of a color image overlapped with afluorescent image on the monitor 6. The color image presents themorphology of the lesion and the fluorescent image presents thefunctional information (information on the degree of malignancy) of thelesion. As shown in FIG. 26, concurrent display allows for the diagnosisof the location and the malignancy of the lesions.

The image processing described above ensures the observation of acurrent condition, such as a cancer of a lesion, without error. Theprocessor 5 calculates or counts the fluorescent peak wavelength signalsand refers to a table of corresponding proteins to the fluorescent peakwavelengths in a memory of the processor 5 to identify the proteinpresent in the living body and stores the identified protein in thememory as data. Thus, individual in vivo protein data can be read fromthe memory and compared with the data in the table of correspondingproteins to reference fluorescent peak wavelengths.

FIGS. 27 and 28 show another embodiment of the rotational disk of thelight source optical system and of the band pass filter attached to thewindows 29 d, 29 e, and 29 f of the rotational disk. Only thedifferences from the rotational disk and band pass filter shown in FIGS.5 and 6 will now be described.

FIG. 27 shows the structure of a rotational disk 23 b and FIG. 28 showsthe spectral transmittance of the band pass filter. As shown in FIG. 27,the rotational disk 23 b has three windows 29 d, 29 e, and 29 f, inwhich are mounted a blue (B) filter (not shown), a green (G) filter (notshown), and a red (R) filter (not shown), respectively. As shown in FIG.28, the B, G, and R filters transmit light in the near-infrared range inaddition to transmitting light in the blue, green, and red wavelengths,respectively.

Table 4 below lists the possible combinations of the band pass filterprovided on the turret 22 and the windows provided in the rotationaldisk 23 b. TABLE 4 Turret 22 Rotational Disk 23b Illumination Lightvisible light mode: 27a 29d, 29e, 29f visible light (B, G, R) infraredmode: 27b 29d, 29e, 29f infrared (excitation light)

Only the B, G, or R light is transmitted and irradiated onto the livingtissue while the band pass filter 27 a that is provided on the turret 22is inserted in the optical path. The excitation light in thenear-infrared range is irradiated onto the living tissue while the bandpass filter 27 b is inserted in the optical path. In this way, therotational filter can be down-sized, thereby enabling the entire lightsource device to be made smaller. Furthermore, with the filter controlmechanism being simplified, the production cost of the light sourcedevice can be reduced.

Another embodiment of the structure of the tunable filter is describedwith reference to FIGS. 29(a)-29(c). In FIGS. 29(a)-29(c), thetransmittance is plotted on the ordinate and the wavelength is plottedon the abscissa. Here, it is assumed that the fluorescent wavelengthsfrom the fluorescent labels are in the range 950-1050 nm. FIG. 29(a)shows the spectral transmittance of the semi-transmitting coatingdeposited on the substrates forming an air gap. In this structure, thespectral transmittance of the semi-transmitting coating is characterizedby a constantly low transmittance over the entire range of wavelengthsin use.

On the other hand, due to interference effects, the spectraltransmittance of the tunable filter periodically has passbands as shownin FIG. 29(b), at least in the wavelength range 400-1100 nm. Thetransmittance peaks occur at wavelengths λ according to the followingequation:2 n_(d) d cos α=mλ  Equation (1)where

-   -   n_(d) is the refractive index of the air gap,    -   d is the thickness of the air gap,    -   α is the angle of incidence of light onto the tunable filter, as        measured from the surface normal,    -   m is the interference order, and    -   λ is the wavelength of a passband peak transmittance.

FIG. 29(c) shows the spectral transmittance when the air gap distance ischanged from a distance A to a distance B, where both the distance A andthe distance B are sufficient for the light to be subject to multipleinterferences. As shown in FIG. 29(c), the wavelengths of the peaktransmittance are shifted, but the peak transmittance amplitudes remainsubstantially constant. The semi-transmitting coating having thespectral transmittance property as shown in FIG. 29(a) can be made of ametal coating formed of deposited silver and aluminum layers, or thecoating can be a dielectric, multi-layered coating.

Light having the spectral intensity properties as shown in FIGS.11(a)-11(c) enters the objective lens 33 and a portion of this light istransmitted through the tunable filter 35 and reaches the lightreceiving surface of the detector 36. The light that reaches thereceiving surface of the detector 36 has the spectral intensityproperties shown FIGS. 30(a)-30(d). In the FIGS. 30(a)-(d), theintensity is plotted in arbitrary units (A.U.) on the ordinate and thewavelength (in nm) is plotted on the abscissa.

As mentioned above, the tunable filter of this exemplary structure has adiscrete property in which the transmission wavelengths in the visiblerange periodically have peaks. This allows partial, narrow ranges ofwavelengths among the reflected light from the living tissue to transmitthrough the tunable filter. The transmission wavelengths of the tunablefilter can be scanned so as to subdivide the light into narrow ranges ofwavelengths. This allows fine analysis of data concerning the livingtissue that is carried by the light that has been reflected from theliving tissue. Needless to say, the tunable filter can be operated todetect plural fluorescent wavelengths in the near-infrared range.

FIGS. 31(a)-31(c) show the spectral transmittance for an exemplarydesign of a two-layer, tunable Fabry-Perot etalon filter. In thisexemplary design, it is assumed that the fluorescence emitted by thefluorescent labels is in the range 950-1050 nm. FIGS. 31(a), 31(b) and31(c) show the spectral transmittance of the tunable filter when the airgap distance d is 1800, 2000, and 2200 nm, respectively.

The reflectance of the reflective coating deposited on the substratesforming the air gap is 90% or more for the light entering the tunablefilter at an incident angle of 0° (as measured from the surface normal).As can be seen in FIGS. 31(a)-31(c), the air gap distance d can bechanged so as to scan the narrow band width passband of the tunablefilter at least in the wavelength range 900-1100 nm.

FIGS. 32(a)-32(c) show the spectral transmittance of an exemplary designof a three-layer, tunable Fabry-Perot etalon filter. In this exemplarydesign, it is assumed that the fluorescence emitted by the fluorescentlabels is in the range 950-1050 nm. This exemplary design is intended toincrease the bandwidth of the passbands within the infrared range so asto improve the S/N ratio of the fluorescent detection.

Furthermore, the reflective coating can have a lower reflectance so asto facilitate manufacture of the coating, thus improving the productionyield in manufacturing the tunable filter. With a three-layer design ofthe tunable filter, the reflective coating needs to have a reflectanceof only 80% or more. The air gap distances d₁ and d₂ can be maintainedidentical while being increased or decreased so that the maximumtransmissions of the passbands in the wavelength range 900-1100 nm aremaintained high and the transmissions in the non-transmission range arelowered.

FIG. 32(a) shows the spectral transmission when d, =d₂=900 nm. Likewise,FIG. 32(b) shows the spectral transmission when both d₁ and d₂ equal1000 nm, and FIG. 32(c) shows the spectral transmission when both d, andd₂ equal 1100 nm. Compared with FIGS. 31(a)-31(c), it can be seen thatthe width of the passbands in the transmission wavelength range 900-1100nm are increased.

The detector (light receiving part) 36 will now be described. Thedetector 36 generally consists of a CCD, CMOS, or highly sensitive imagepickup element. Highly sensitive image pickup elements can be preferablyused in the present invention particularly because very weak light, suchas fluorescence, is detected. FIGS. 33-36 show an embodiment in which acharge multiplying solid-state image pickup element is used as a highlysensitive image pickup element.

FIG. 33 is an illustration of the structure of a charge multiplyingsolid-state image pickup element.

FIG. 34 is a timing chart of a sensitivity control pulse CMD (ChargeMultiplying Detector) and of the horizontal transfer pulses S1 and S2.

FIG. 35 shows the sensitivity (i.e., the multiplication factor) of thecharge multiplying solid-state image pickup element of the CMD versusthe applied voltage.

FIG. 36 is a timing chart for driving the charge multiplying solid-stateimage pickup element. The various signals (a)-(j) can be decoded usingTable 5 below. TABLE 5 Signal Meaning or Operation (a) action of therotational filter during the ordinary light observation mode (b)vertical transfer pulses P1, P2 during the ordinary light observationmode (c) horizontal transfer pulses S1, S2 during the ordinary lightobservation mode (d) sensitivity control signal for the CMD during theordinary light observation mode (e) CCD output signal (exposure/cut-off)during the ordinary light observation mode (f) action of the rotationalfilter during the special light observation mode (g) vertical transferpulses P1, P2 during the special light observation mode (h) sensitivitycontrol pulses for the CMD during the fluorescent light observation mode(i) sensitivity control pulses for the CMD during the fluorescent lightobservation mode (j) CCD output signal during one cycle of thefluorescent light observation mode

The solid-state image pickup element (hereinafter referred to as a CCD)is provided with a charge multiplying part between the horizontaltransfer path and an output amplifier or at individual pixels in theelement. An intensive pulse electric field is applied to the chargemultiplying part from the processor so that signal charges acquireenergy from the electric field and collide with electrons in the valenceband. This causes impact ionization at first and then produces newsignal charges (secondary electrons). The charge multiplying part may beimplemented using, for example, a charge multiplying solid-state imagepickup element as described in U.S. Pat. No. 5,337,340, entitled “ChargeMultiplying Detector (CMD) Suitable for Small Pixel CCD Image Sensors”,the disclosure of which is hereby incorporated by reference.

For example, the pulses may be applied to produce secondary electrons ina chain reaction avalanche effect. Pulses with relatively low voltagecompared to those for an avalanche effect are applied to produce a pairof electron-positive holes in the impact ionization. When the chargemultiplying part is provided before the output amplifier in a CCD, thepulse voltage value (amplitude) or pulse number applied can becontrolled in a lump so as to multiply the number of signal charges inan arbitrary manner.

On the other hand, when the charge multiplying parts are provided toindividual pixels, the pulse voltage value (amplitude) or pulse numberapplied can be controlled pixel-by-pixel so as to multiply the number ofsignal charges in an arbitrary manner. The CCD in this embodiment is anFFT (Full Frame Transfer) type monochrome CCD in which the chargemultiplying part is mounted between the horizontal transfer path and theoutput amplifier.

Referring to FIG. 33, the CCD includes an image area 60 of the lightreceiving part, an OB (Optical Black) part 61, a horizontal transferpath 62, a dummy 63, a charge multiplying part 64, and an outputamplifying part 65. The charge multiplying part 64 includes a number ofcells, with the number of cells being in the range from approximatelyequal to the number of horizontal transfer paths 62 to twice the numberof horizontal transfer paths 62. The CCD may be an FT (Frame Transfer)type having a charge storage part.

The signal charges produced at individual pixels of the image area 60are transferred to the horizontal transfer path 62 one horizontal lineat a time according to vertical transfer pulses P1 and P2 and are thentransferred from the horizontal transfer path 62 to the dummy 63 and tothe charge multiplying part 64 according to horizontal transfer pulsesS1 and S2. When a sensitivity control pulse CMD is applied to individualcells forming the charge multiplying part 64, the charge is sequentiallymultiplied in being transferred from one cell to another as far as tothe output amplifying part 65. The output amplifying part 65 convertsthe charge from the charge multiplying part 64 to a voltage so as toproduce an output signal.

The sensitivity multiplication rate obtained by the charge multiplyingpart 64 is modified by changing the voltage value (amplitude) of thesensitivity control pulse CMD to the charge multiplying part 64 from theCCD driving circuit. The charge multiplying part 64 executes chargemultiplication at every cell. The sensitivity multiplication rateobtained by the charge multiplying part 64 is characterized in that thecharge multiplication starts when the applied voltage exceeds a certainthreshold Vth and the sensitivity is exponentially multipliedthereafter, as shown in FIG. 35.

The CCD driving circuit varies the voltage value (amplitude) of thesensitivity control pulse CMD shown in FIG. 36(i) based on the datasupplied by the sensitivity control circuit, and outputs the sensitivitycontrol pulse CMD that is synchronized with the horizontal transferpulses S1 and S2, shown in FIG. 36(h), in phase to the CCD. In thismanner the CCD driving circuit changes the voltage value (amplitude) ofthe sensitivity control pulse CMD signal that is applied to the chargemultiplying part 64 so as to achieve a desired sensitivitymultiplication rate. Using an image pickup element as described above asthe detector 36 enables the detection of the fluorescence, which issignificantly weaker than the reflected light, with a high S/N ratio.

FIG. 39 is a block diagram to show the configuration of anotherembodiment of the present invention. In this embodiment, a dichroicprism is used in place of the tunable filter described with reference toFIG. 12 as the wavelength separation element for separating thefluorescent wavelengths produced by the fluorescent labels. In FIG. 39,the near-infrared wavelengths transmitted through the excitation lightcut-off filter are separated by the dichroic prism into individualwavelengths, which are individually detected by a CCD. In the embodimentshown in FIG. 39, the reflected light from a subject and thefluorescence are imaged by an eyepiece lens provided at the tip of alight guide fiber 132. The images are transferred to the rear endsurface via the light guide fiber 132 and supplied to a camera head 100attached to the endoscope by an imaging lens 121. Light entering thecamera head 100 is separated into infrared and visible light componentsby a dichroic mirror 122. The infrared component reflected by thedichroic mirror 122 enters a first dichroic prism 125 via an excitationlight cut-off filter 123.

The excitation light cut-off filter 123 eliminates the excitation lightcomponent and transmits the fluorescent component in the infrared range.The first dichroic prism 125 separates the incident light into threespecific fluorescent wavelengths and leads them to CCDs 124 a, 124 b,and 124 c, respectively. The CCDs 124 a, 124 b, and 124 c detectdifferent fluorescent wavelengths. In this way, the image of thefluorescent components produced by the fluorescent labels can bedetected by the CCDs 124 a, 124 b, and 124 c.

The lengths and number of components of wavelengths separated by thefirst dichroic prism 125 can be determined by the optical property ofthe prism in an arbitrary manner. In FIG. 39, as described above, theexcitation light cut-off filter 123 blocks the excitation lightwavelengths and transmits the fluorescent wavelengths. The firstdichroic prism 125 and CCDs 124 a-124 c correspond to a detection meansincluding the wavelength separation element for separating fluorescentwavelengths produced by plural fluorescent labels and plural detectionelements for detecting individual fluorescent wavelengths separated bythe wavelength separation element.

The visible light component transmitted through the dichroic mirror 122is supplied to a second dichroic prism 129 and a camera that includesthree CCDs 126, 127 and 128. The second dichroic prism 129 separates theincident light into red (R), green (G), and blue (B) components andleads them to CCDs 126, 127, and 128, respectively. In this way,ordinary visible image (ordinary optical image) components can beobtained by the CCDs 126, 127, and 128. CCDs 124 a-124 c and CCDs126-128 are synchronously driven by a CCD driving circuit (not shown).

Electric signals from the CCDs 124 a-124 c and CCDs 126-128 are suppliedto a pre-process circuit 152 of the processor 5 b where adjustments aremade for gain by an amplifier and for white balance of visible lightimages by a white-balance correction circuit, which are not shown. Then,the signals are supplied to an A/D converter 153 where analog signalsare converted to digital signals. The digital signals from the A/Dconverter 153 are supplied to an image signal processing circuit 154 andtemporarily stored in an image memory. Subsequently, they are subject toimage processing, such as image enhancing and noise elimination, anddisplay controls for concurrent display of a fluorescent image, a colorimage, and character information.

The image signal processing circuit 154 further executes a process fordisplaying a fluorescent image overlapped with an ordinary optical imageor a process that normalizes the fluorescent image using data of thecolor and fluorescent images. This provides a fluorescent image that iseasy to identify when presented with an ordinary image. The digitalsignals from the image signal processing circuit 154 are supplied to aD/A converter 155 where they are converted to analog signals. The analogsignals are supplied to the monitor 160 for display.

On the monitor, several choices are available: two images, ordinarylight and fluorescent, may be displayed concurrently side-by-side in thesame size or in different sizes; two images may be overlapped; orprocessed images of fluorescent and ordinary light images may bedisplayed. Thus, a fluorescent image and an ordinary observation imagecan be viewed simultaneously. Therefore, the fluorescent image andordinary observation image may be obtained with no time lag, enablingthe locating of a lesion in a simple and highly accurate manner, whichis a significant advantage in facilitating a proper diagnosis.

The excitation light cut-off filter 123, a first dichroic prism 125,three CCDs 124 a, 124 b, and 124 c, and a detection means that includesa wavelength separation element for separating fluorescent wavelengthsproduced by plural fluorescent labels and plural detection elements fordetecting individual fluorescent wavelengths separated by the wavelengthseparation element are provided at the eyepiece of an endoscope. Inother embodiments of the present invention, these members can beprovided at the tip of an endoscope.

An excitation light cut-off filter 123 having the transmittance shown inFIG. 10 may be used as a means for eliminating the excitation lightcomponent while transmitting the fluorescent components in the infraredrange. In the exemplary structure of FIG. 39, the first dichroic prism125 serves as a wavelength separation element that automaticallyseparates fluorescent wavelengths without any controls, which simplifiesthe structure of the endoscope.

With the transmittance being separated by wavelengths, the processor 5 bcalculates or counts the fluorescent peak wavelengths and displaysimages in pseudo-colors according to the count obtained. With thetransmitted light being separated by wavelengths, the fluorescent peakwavelengths are calculated or counted and reference is made to a tableof the corresponding proteins which exhibit a similar profile offluorescent peak wavelengths in a memory (not-shown) of the processor 5b so as to identify the protein present in the living body and to storethis information as data in the memory.

In this way, images may be displayed in pseudo-colors, depending on thecount, and the current condition of a lesion, such as whether it iscancerous, can be reliably diagnosed. Furthermore, individual in vivoprotein data can be read from memory and compared with data in a tableof corresponding proteins by referencing the peak transmittancewavelengths in the fluorescence.

The fluorescent wavelengths of quantum dots used as fluorescent labelscan be made to have a desired Gaussian distribution by adjusting thematerials and outer diameters of the quantum dots, as shown in FIG. 38.For example, for a blue series, Cd Se nano-crystals can be used withdiameters of 2.1, 2.4, 3.1, 3.6, or 4.6 nm. For a green series, InPnano-crystals can be used with diameters of 3.0, 3.5, or 4.6 nm. For ared series, InAs nano-crystals can be used having diameters of 2.8, 3.5,4.6, or 6 nm.

As described above, the present invention allows the use of quantum dotsas fluorescent labels (tags) made from CdSe, InP, or InAs and havingvarious diameters depending on the number of living subjects (proteins)to be identified, and with diameters in the range 2.1-6.0 nm. Thequantum dots having plural different diameters are synthesized so as tohave hydrophilicity, antibody properties, and to be bio-compatible. Inaddition, the materials and the outer diameters may be selected so as toprovide optimized spectral properties regarding infrared excitationlight and infrared fluorescence.

The quantum dots are used as fluorescent labels in this embodiment.However, materials that are excited with red or near-infrared lightwhich reaches the deep portion of the living tissue and materials thatemit fluorescent light lying in the near-infrared region are alsoapplicable as fluorescent label materials in the diagnostics using theendoscope system according to the present invention. The fluorescentlabels (tags), such as the quantum dots, that are excited with red ornear-infrared light which reaches the deep portion of the living tissueand that emit fluorescent light lying in the near-infrared region may beintroduced into living tissue and then irradiated by excitation light soas to cause fluorescence in the near-infrared wavelength range. Thisallows the detection of cancer in the earliest stage even deep insideliving tissue. In this way, the present invention enables fluorescentlabels that have been introduced into living tissue to be used todiagnose cancer in its earliest stage.

FIGS. 40-42 show alternative embodiments of the entire structure of theendoscope system according to the present invention wherein thestructure that separates and detects plural fluorescent wavelengths ispositioned other than in the endoscope tip. As the individual componentsare numbered identically with those of FIG. 1, only the differences willbe now be described. FIG. 40 shows the overall structure of a secondembodiment of an endoscope system according to the present invention,characterized by having the components that separate and detect pluralfluorescent wavelengths within the endoscope tip of the type that usesan optical fiber (fiberscope). Whereas in FIG. 1 the optical elementsincluding the excitation light cut-off filter 34 are positioned justafter the objective lens 33, in FIG. 40 a fiber bundle (a so-calledimage guide fiber bundle) is arranged just after the objective lens, andan ocular lens is provided at the exit side of the fiber bundle. Thedetection optical elements, which have a similar structure to those inFIG. 1, may be arranged in a separate housing from that which houses theinsertion section and ocular lens.

FIG. 41 illustrates a minor change from that illustrated in FIG. 40.Whereas in FIG. 40 the excitation light cut-off filter 34 is arrangedwithin the ocular lens, in FIG. 41 it is arranged outside the ocularlens by being positioned within the insertion section between theoptical fiber bundle and the ocular;

FIG. 42 also illustrates a minor modification from FIG. 40. In FIG. 40the optical elements are arranged at the exit side of an ocular lens soas to be outside the insertion section. On the other hand, in FIG. 42,the housing of the optical elements is united with the fiber scope(i.e., all optical elements are arranged within the insertion section).Whereas in FIG. 40 the optical elements for separating and detectingplural fluorescent light sources are arranged at the exit side of theocular lens, in FIG. 42 these same optical elements are united withinthe housing of the fiberscope (i.e., all optical elements are arrangedin the housing of the insertion portion of the endoscope);

FIG. 43 shows another embodiment of the present invention. Only thedifferences with regard to FIG. 43 will be described as compared to FIG.39. In this embodiment, a tunable filter 35 and a detector 36 are usedas in FIG. 1 as a wavelength separation element for separatingfluorescent wavelengths emitted by the fluorescent labels in lieu ofusing a dichroic prism 125 and the three CCDs 124 a, 124 b, and 124 cshown in FIG. 39. Furthermore, a color CCD 202 is used in lieu of thesecond dichroic prism 129 for detecting visible light components and theplural-circuit-board camera that uses the three CCDs 126, 127, and 128.Thus, the number of CCDs used at the camera head can be significantlyreduced and this not only makes for a more compact design but also theendoscope has reduced cost. Also with this structure, the same detectionability of visible and fluorescent light as the endoscope system havingthe structure shown in FIG. 39 can be obtained. The color CCD 202 can bereplaced by a monochrome CCD. In such a case, the light source unit 2emits the light in a sequential manner as in embodiment 1.

FIG. 44 shows another embodiment of the present invention. Again, onlythe differences relative to the structure shown in FIG. 1 will bedescribed. In this embodiment, an endoscope optical system 3 thatutilizes two observation optical systems, one observation optical systemfor detecting only wavelengths of light in a band that corresponds to anemitted fluorescence, and a second observation optical system fordetecting only visible light.

The observation optical system for detecting only visible light isformed of an objective lens 200, a visible light transmitting filter203, and a CCD 201. The visible light transmitting filter 203 isdifferent from the visible light transmitting filter 27 a only in termsof its outer diameter.

The observation optical system for detecting only wavelengthscorresponding to those of an emitted fluorescence is different from thatof FIG. 1 in that it uses an infrared transmitting filter 204 having aspectral transmittance as shown in FIG. 45 in lieu of using theexcitation light cut-off filter 34 shown in FIG. 1. The detector 36detects only wavelengths corresponding to an emitted fluorescence. Thus,the detector 36 can be a highly sensitive detector that detects onlyinfrared light. The morphology (i.e., structure) of an observation siteis obtained by using a CCD 201 that detects visible light components.The detector 36 can be a photo-electric sensor made, for example, of PbSthat is highly sensitive to infrared wavelengths instead of visiblewavelengths (the latter are normally detected with an image pickupelement that uses, for example, a CCD). This allows for improved S/N inthe detection of fluorescent components, which are significantly weakerthan the light emitted in the visible region. The endoscope system ofthis embodiment enables one to observe a visible image and a fluorescentimage simultaneously by irradiating illumination lights for visibleobservation and for fluorescent observation at the same time. In thiscase, the structure of the illumination optical system 2 is simplified.

FIGS. 46 and 47 show another embodiment of the present invention. Inthis embodiment, the function of the endoscope system described withregard to FIG. 1 is realized in a capsule endoscope. In FIG. 46, thesame items have been labeled with the same reference numbers and thusonly the differences will be discussed.

In FIG. 46, a capsule endoscope apparatus 300 includes light emittingelements 301-304 (such as LED's), a lens 33 for collecting light thathas been reflected from a living body (e.g. an examination subject) orfluorescence, an excitation light cut-off filter 34, a tunable filter 35and a detector 36. The lens 33 has an optical axis CL. The lightemitting elements 301 to 304 are asymmetrically provided in relation tothe optical axis CL.

The capsule endoscope apparatus 300 also comprises a control circuit305, a power source 306 such as a capacitor and a battery, a coil 307that is electrically connected to the power source 306, a magnet 308,and antenna 309, and a transmitter 310. A transparent cover 311transmits the emitted light from the light emitting elements 301-304 soas to illuminate the living body and introduces the reflected light orfluorescence into the lens 33. A case 312 is also shown. When the magnet308 is magnetized by externally provided magnetic field lines, the coil307 generates electric current due to magnetic induction so as to chargethe capacitor or battery of the power source 306. The magnet 308 servesas an energy source to move the capsule endoscope apparatus 300 usingexternally provided electromagnetic waves. The antenna 309 transmitsdetection signals of the detector 36 to an external unit. Thetransmitter 310 transmits information on the current position of thecapsule endoscope apparatus 300 to an external unit that, together withthe endoscope apparatus 300, forms a capsule endoscope system.

The external unit 313 has a transmission/reception antenna 314 and amonitor 315. It also has a control circuit, not shown. Thetransmission/reception antenna 314 receives signals transmitted from theantenna 309 and transmitter 310 of the capsule endoscope apparatus 300.It also transmits electromagnetic waves or magnetic energy to the magnet308. The monitor 315 displays images that are formed based on thedetection signals of the detector 36 transmitted from the antenna 309.

FIG. 47 is an end view of the front end of the capsule endoscopeapparatus as viewed from a position on the optical axis. The lightemitting elements 301, 302, and 303 emit blue, green, and red light,respectively. The light emitting element 304 emits infrared light havingwavelengths including part of the wavelength range from 600 to 2000 nmthat comprises the excitation light wavelength of the fluorescentlabels. A different detection system from that used in the endoscopesystem shown in FIG. 1 is used for detecting the wavelengths ofreflected visible light versus fluorescence from a living body.

The endoscope apparatus shown in FIG. 1 uses band pass filters havingdifferent properties and that are provided in the light source opticalsystem 2 for selecting the wavelengths of the illumination light thatilluminates the living body tissue. In this embodiment, as shown in FIG.47, multiple light emitting elements having different wavelengths, suchas LED's, are used in lieu of using the light source optical system 2.The control circuit 305 is used to intermittently energize multiple LEDs301 to 304 that emit different wavelengths sequentially so as to utilizethe same illumination system as the light source optical system 2. Inthis manner, the capsule endoscope system of the present invention canseparately detect visible light that is reflected by the living tissueversus fluorescence that is emitted by the fluorescent labels. Inaddition, by using a capsule endoscope that employs wireless technologyin lieu of, for example, using an insertion-type endoscope as shown inFIG. 1 (i.e., one that is hard-wired) the pain experienced by a patientduring an endoscopic examination can be reduced.

The present invention enables the user to provide advanced (i.e., early)diagnosis including diagnosis of the malignancy of lesions using anendoscope system than previously available in prior art endoscopesystems. Using quantum dots for fluorescent markers in conjunction withthe endoscope system of the present invention allows for more than onehour of endoscopic observation, as the fluorescence from quantum dotshas a prolonged emission time period and is bright. Moreover, thefluorescence emitted by quantum dots has a narrow wavelength range,Gaussian distribution, and thus is suitable for detection by an tunablefilter, such as a Fabry-Perot etalon type, band pass filter.

The invention being thus described, it will be obvious that the same maybe varied in many ways. For example, the combinations of the excitationlight cut-off filters and tunable filter(s) are not restricted thosedescribed above. And, as is apparent from the various embodimentsdiscussed above, many modifications are allowed in the endoscopic systemused while practicing the basic concept of the invention. Thus,variations from the specific embodiments discussed above are not to beregarded as a departure from the spirit and scope of the invention.Rather, the scope of the invention shall be defined as set forth in thefollowing claims and their legal equivalents. All such modifications aswould be obvious to one skilled in the art are intended to be includedwithin the scope of the following claims.

1. An endoscope system for detecting fluorescent light emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced into a living tissue, comprising: an endoscope that has anelongated insertion section and an eyepiece section; an illuminationsystem for generating illumination light that includes an excitationlight for said plurality of fluorescent labeling materials; a detectionsystem that includes an optical element having a transmission wavelengththat can be varied so as to separate fluorescent light emissions thatare emitted at different wavelengths from among the plurality offluorescent labeling materials, said optical element located in theeyepiece section; and a controller that controls the transmissionwavelength of said optical element so as to scan for differentfluorescent light emissions.
 2. An endoscope system for detectingfluorescent light emitted in the near-infrared region by a plurality offluorescent labeling materials introduced into a living tissue,comprising: an endoscope that has an elongated insertion section; anillumination system for generating illumination light that includes anexcitation light for said plurality of fluorescent labeling materials; adetection system that includes an optical element having a transmissionwavelength that can be varied so as to separate fluorescent lightemissions that are emitted at different wavelengths from among theplurality of fluorescent labeling materials, said optical elementlocated in a distal end part of said elongated insertion section; and acontroller that controls the transmission wavelength of said opticalelement so as to scan for different fluorescent light emissions.
 3. Theendoscope system according to claim 2, wherein said excitation lightincludes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.
 4. Anendoscope system for detecting fluorescent light emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced into a living tissue, comprising: an endoscope having aninsertion section and an eyepiece section; an illumination system forgenerating illumination light that includes an excitation light for theplurality of fluorescent labeling materials; a detection system thatincludes an electronic camera head adapted to be optically connected tosaid eyepiece section and an optical element which separates fluorescentlight emissions that are emitted at different wavelengths from among theplurality of fluorescent labeling materials, said optical elementlocated in the camera head; and a plurality of sensors that receive therespective separated fluorescent light emissions that are emitted atdifferent wavelengths.
 5. The endoscope system according to claim 4,wherein said excitation light includes wavelengths in the wavelengthrange of 600 nm≦λ≦2000 nm.
 6. The endoscope system according to claim 1,the detection system further including a filter that cuts off theexcitation light.
 7. The endoscope system according to claim 2, thedetection system further including a filter that cuts off the excitationlight.
 8. The endoscope system according to claim 2, the detectionsystem further including an objective optical system and a filter thatcuts off the excitation light, said objective optical system and saidfilter located in a distal end portion of the insertion section.
 9. Theendoscope system according to claim 4, the detection system furtherincluding an objective optical system and a filter that cuts off theexcitation light, said objective optical system and said filter locatedin a distal end portion of the insertion section.
 10. The endoscopesystem according to claim 1, wherein said optical element is an etalon.11. The endoscope system according to claim 2, wherein said opticalelement is an etalon.
 12. The endoscope system according to claim 1,wherein: the illumination system comprises a light source device thatincludes a plurality of wavelength selection filters that are insertableinto, and removable from, an optical path of the illumination light; andthe illumination system has at least two illumination modes, namely,mode 1 and mode 2, that are selectable by inserting, and/or removing,one or more of the plurality of filters; where in mode 1, illuminationlight is emitted only within the visible region; and in mode 2,illumination light having a wavelength component λ within the range 600nm≦λ≦2000 nm is emitted.
 13. The endoscope system according to claim 12,wherein said optical element has its transmission wavelength varied bychanging a voltage applied to said optical element only in mode
 2. 14.The endoscope system according to claim 2, wherein: the illuminationsystem includes a light source device having a plurality of wavelengthselection filters that are insertable into, and removable from, anoptical path of the illumination light; and the illumination system hasat least two illumination modes, namely, mode 1 and mode 2, that areselectable by inserting, and/or removing, one or more of the pluralityof filters; where in mode 1, illumination light is emitted only withinthe visible region; and in mode 2, illumination light having awavelength λ component within the range 600 nm≦λ≦2000 nm is emitted. 15.The endoscope system according to claim 14, wherein said optical elementhas its transmission wavelength varied by changing a voltage appliedthereto only in the mode
 2. 16. The endoscope system according to claim4, wherein: the illumination system comprises a light source device thatincludes a wavelength selection filter that is insertable into, andremovable from, an optical path of the illumination light, saidwavelength selection filter transmits or reflects, at least a part,wavelengths of illumination light in the range of approximately 600nm-2000 nm, and the fluorescence separation optical element isconfigured so as to separate the fluorescences only when a specifiedfilter is inserted into the illumination light path.
 17. An endoscopesystem for detecting fluorescences in the near-infrared region by aplurality of fluorescent labeling materials that have previously beenintroduced into a living tissue, comprising: an illumination system forgenerating illumination light that includes light for excitation of theplurality of fluorescent labeling materials, or visible light; adetection system that includes an excitation light cut-off filter, awavelength separation filter that separates the fluorescences emittedfrom the plurality of fluorescent labeling materials, and a sensor thatdetects sequentially each of the separated fluorescences; and aobservation system that includes an objective optical system and animage sensor for receiving an image of an object formed by the objectiveoptical system.
 18. The endoscope system according to claim 17, whereinsaid excitation light includes wavelengths in the wavelength range of600 nm≦λ2000 nm.
 19. The endoscope system according to claim 17, whereinthe sensor serves as both a fluoresence detector and an image sensor.20. An endoscope system for detecting fluorescences emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced in a living tissue, comprising: an illumination system; anobservation system; and a TV camera unit; wherein the illuminationsystem includes a light source device which generates illumination lightthat includes light for excitation of the plurality of fluorescentlabeling materials; the observation system includes an objective opticalsystem, an image transmitting optical system that transmits an imageformed by the objective optical system, and an ocular optical system;and the TV camera unit includes a coupling optical system adapted to beoptically connectable to the ocular optical system for forming an imageof the image transmitted by the transmission optical system, anexcitation light cut-off filter, a wavelength separation filter thatseparates the fluorescences emitted from the plurality of fluorescentlabeling materials, and an image sensor.
 21. The endoscope systemaccording to claim 20, wherein said excitation light includeswavelengths in the wavelength range of 600 nm≦λ≦2000 nm.
 22. Anendoscope system for detecting fluorescences emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced into living tissue, comprising: an illumination system; anobservation system; and a TV camera unit; wherein the illuminationsystem includes a light source device which generates illumination lightthat includes light for excitation of the plurality of fluorescentlabeling materials; the observation system includes an objective opticalsystem, an image transmitting optical system that transmits an imageformed by the objective optical system, and an ocular optical systemthat includes an excitation light cut-off filter; and the TV camera unitincludes a coupling optical system adapted to be optically connectableto the ocular optical system for forming an image of the imagetransmitted by the transmission optical system, a wavelength separationfilter that separates the fluorescences emitted from the plurality offluorescent labeling materials, and an image sensor.
 23. The endoscopesystem according to claim 22, wherein said excitation light includeswavelengths in the wavelength range of 600 nm≦λ≦2000 nm.
 24. Anendoscope system for detecting fluorescences emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced into living tissue, comprising: an endoscope; and a lightsource device; wherein the light source device generates illuminationlight that includes light for excitation of the plurality of fluorescentlabeling materials; the endoscope comprises an objective optical system,an image transmission optical system that transmits an image formed bythe objective optical system, a coupling optical system that forms animage of the image transmitted by the transmission optical system, animage sensor, an excitation light cut-off filter, and a wavelengthseparation filter that separates the fluorescences emitted by theplurality of fluorescent labeling materials; and both the excitationlight cut-off filter and the wavelength separation filter are arrangedbetween the transmission optical system and the image sensor.
 25. Theendoscope system according to claim 24, wherein said excitation lightincludes wavelengths in the wavelength range of 600 nm≦λ≦2000 nm.
 26. Acapsule endoscope apparatus for detecting fluorescences emitted in thenear-infrared region by a plurality of fluorescent labeling materialsintroduced into living tissue, the capsule endoscope apparatuscomprising: an illumination unit that includes a red band light source,a green band light source, a blue band light source, and a near-infraredband light source; and an imaging unit that includes an objectiveoptical system, an excitation light cut-off filter, a transmissionwavelength separation filter which separates different fluorescencesemitted from different fluorescent labeling materials, and an imagesensor.
 27. A capsule endoscope system that includes the capsuleendoscope apparatus according to claim 26, wherein the capsule endoscopeapparatus further includes a transmitter; and a receiver is providedoutside the capsule endoscope apparatus for receiving an image signaltransmitted by the transmitter.
 28. The capsule endoscope systemaccording to claim 27, and further including an image display devicepositioned outside the capsule endoscope apparatus that displays anendoscopic image using reflected visible wavelength light and on whichmarks, that indicate positions where the fluorescences are emitted bythe living tissue, are superimposed.
 29. The capsule endoscope systemaccording to claim 28, wherein the displayed marks are different colors,each different color corresponding to a different fluorescent labelingmaterial.
 30. An endoscope system for detecting fluorescences emitted bya plurality of different fluorescent labeling materials introduced intoliving tissue, comprising: an illumination system; and an observationsystem; wherein the illumination system includes illumination optics anda light source device that generates at least light for normalobservation and light for excitation of the fluorescent labelingmaterials; the observation system includes an objective optical system,an excitation light cut-off filter, a wavelength tunable filter, and adetector; and the wavelength tunable filter is a tunable etalon that hasan average transmittance in the visible region that enables a sufficientintensity of light to transmit through the wavelength tunable filter fornormal observation, and has a narrow passband in the infrared regionwith the passband, as well as the passband wavelength peak, beingvariable in wavelength.
 31. An endoscope system for detectingfluorescences emitted by a plurality of fluorescent labeling materialsintroduced into living tissue, comprising: an illumination system; andan observation system; wherein the illumination system generates anexcitation light for the fluorescent labeling materials; the observationsystem includes an objective optical system, an excitation light cut-offfilter, a wavelength tunable filter and a detector; the tunable filteris formed as an etalon that includes a plurality of transparentsubstrates arranged so as to form a gap therebetween, the surfaces ofthe substrates that face each other across the gap have semi-transparentfilms, at least two of which have a spectral transmittance and thefollowing conditions are satisfied: T1≧80% and T2≦35%, where T1 is theaverage transmittance in the wavelength region of 400 nm≦λ≦650 nm, andT2 is a transmittance in the wavelength band having a lower boundarythat is 50 nm shorter than the peak transmittance wavelength of theshortest fluorescence wavelength, and an upper boundary that is 50 nmlonger than the peak transmittance wavelength of the longestfluorescence wavelength.
 32. An endoscope for detecting fluorescenceemitted by a plurality of fluorescent labeling materials introduced intoliving tissue, comprising: an illumination unit; and an observationunit; wherein the illumination unit generates near-infrared illuminationlight that includes a wavelength band for excitation of the fluorescentlabeling materials; the observation unit includes an objective opticalsystem, an excitation light blocking filter, a wavelength tunablefilter, and a detector; the combination of the excitation light blockingfilter and the tunable filter passes light in the visible region, andhas a passband in the infrared region which allows the fluorescenceemitted from the fluorescent labeling material that is under observationto pass through; wherein the spectral transmittance of said combinationsatisfies the following conditions: T3≧60% T4≦0.01% T5≧65% 5 nm≦d5≦35 nmwhere T3 is the average transmittance within the visible wavelengthrange of 400 nm≦λ≦650 nm, T4 is the transmittance for the wavelengthswithin a range 20 nm above and 20 nm below the wavelength range of theexcitation light generated by the illumination unit, T5 is thetransmittance at the peak transmittance wavelength for an infraredpassband, d5 is the infrared passband's full width as measured at 50% ofthe peak transmittance, and λ is the wavelength of light incident ontothe filter.
 33. The endoscope system according to claim 30, wherein thetunable etalon includes at least three semi-transparent base substrates.34. The endoscope system according to claim 31, wherein the etalonincludes at least three semi-transparent base substrates.
 35. Theendoscope system according to claim 32, wherein the tunable filterincludes at least three semi-transparent base substrates.
 36. Theendoscope system according to claim 1, and further comprising an imagedisplay device that displays an endoscopic image of the living tissue onwhich marks, that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 37. The endoscope systemaccording to claim 2, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 38. The endoscope systemaccording to claim 4, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 39. The endoscope systemaccording to claim 17, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 40. The endoscope systemaccording to claim 20, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 41. The endoscope systemaccording to claim 22, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 42. The endoscope systemaccording to claim 24, and further comprising an image display devicethat displays an endoscopic image of the living tissue on which marks,that indicate the positions on the living tissue from whichfluorescences are detected, are superimposed.
 43. The endoscopeaccording to claim 1, wherein said excitation light includes wavelengthsin the wavelength range of 600 nm≦λ≦2000 nm.